Method for Treating Nervous System Injuries Using Boldine and Analogs Thereof

ABSTRACT

Provided are methods of treating an injury to the nervous system in a subject comprising administering to the subject an effective amount of boldine, a boldine analog, or a pharmaceutically-acceptable salt thereof. Also provided are methods of improving voluntary muscle control and methods of treating neuropathic pain in a subject having an injury to the nervous system. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present disclosure.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/971,757, filed Feb. 7, 2020, and U.S. Provisional Application No.63/043,572, filed Jun. 24, 2020, both of which are incorporated byreference in their entirety.

BACKGROUND

The mammalian nervous system comprises a peripheral nervous system (PNS)and a central nervous system (CNS, comprising the brain and spinalcord), and is composed of two principal classes of cells: neurons andglial cells. The glial cells fill the spaces between neurons, nourishingthem and modulating their function. Certain glial cells, such as Schwanncells in the PNS and oligodendrocytes in the CNS, also provide aprotective myelin sheath that surrounds and protects neuronal axons,which are the processes that extend from the neuron cell body andthrough which the electric impulses of the neuron are transported. Inthe peripheral nervous system, the long axons of multiple neurons arebundled together to form a nerve or nerve fiber. These, in turn, may becombined into fascicles, wherein the nerve fibers form bundles embedded,together with the intraneural vascular supply, in a loose collagenousmatrix bounded by a protective multilamellar sheath. In the centralnervous system, the neuron cell bodies are visually distinguishable fromtheir myelin-ensheathed processes, and are referenced in the art as grayand white matter, respectively.

The nervous system stimulates many tissues in the body and by doing soaffects the perception of pain, joint position, muscle tension, hot andcold sensations, pulse, blood pressure, salivation, eye function,intestine function, among other physiological processes. Similarly,nerves transmit impulses by which the brain signals which muscles tocontract. Accordingly, the neural pathways of a mammal are particularlyat risk if neurons are subjected to trauma.

Injuries to the nervous system frequently disrupt nerve function andinterfere with various physiological processes regulated or controlledby nerves. Injuries to the central nervous system, for example, such asa spinal cord injury (SCI), can be devastating, often resulting inparalysis, loss of sensation, dysregulation of the automatic nervoussystem, and inability to regain voluntary control of muscles. Likewise,traumatic brain injury (TBI), often caused by blunt trauma, oftenresults in immediate neuronal, axonal, and vascular destruction.Peripheral nerve injuries, such as a crushed nerve as a result oftrauma, can also result in disruption to nervous system function.Finally, nervous system injuries often lead to secondary conditions suchas neuropathic pain, which is difficult to ameliorate with conventionalpain medications, in addition to loss or impairment of voluntary musclecontrol and locomotor function.

Though strides have been made toward addressing complications of nervoussystem injuries, such as pulmonary or bladder complications, there is nocell-based or pharmacologic approach to consistently improve sensory ormotor function after a traumatic injury to the nervous system. Thus,there remains a need for effective treatment of various injuries to thenervous system, as well as secondary conditions that may arise from suchinjuries, including neuropathic pain. These needs and others are met bythe following disclosure.

SUMMARY

In one aspect, this disclosure relates to a method of treating an injuryto the nervous system in a subject, comprising administering to thesubject an effective amount of a compound represented by the formula:

wherein R¹ is selected from hydrogen and C1-C4 alkyl; wherein R² isselected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; wherein each of R³ and R⁴ isindependently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl; or wherein R³ and R⁴ join together to form a ring having 5-7atoms; wherein each of R⁵ and R⁶ is independently selected fromhydrogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; or wherein R⁵ and R⁶join together to form a ring having 5-7 atoms; and wherein R⁷ isselected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; or a pharmaceutically-acceptablesalt thereof, thereby treating the injury to the nervous system in thesubject.

In a further aspect, the disclosure relates to a method of improvingvoluntary muscle control in a subject having an injury to the nervoussystem, comprising administering to the subject an effective amount of acompound represented by the formula:

wherein R¹ is selected from hydrogen and C1-C4 alkyl; wherein R² isselected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; wherein each of R³ and R⁴ isindependently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl; or wherein R³ and R⁴ join together to form a ring having 5-7atoms; wherein each of R⁵ and R⁶ is independently selected fromhydrogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; or wherein R⁵ and R⁶join together to form a ring having 5-7 atoms; and wherein R⁷ isselected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; or a pharmaceutically-acceptablesalt thereof, thereby improving voluntary muscle control in the subject.

In a further aspect, disclosed is a method of treating neuropathic painin a subject having an injury to the nervous system, comprisingadministering to the subject an effective amount of a compoundrepresented by the formula:

wherein R¹ is selected from hydrogen and C1-C4 alkyl; wherein R² isselected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; wherein each of R³ and R⁴ isindependently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl; or wherein R³ and R⁴ join together to form a ring having 5-7atoms; wherein each of R⁵ and R⁶ is independently selected fromhydrogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; or wherein R⁵ and R⁶join together to form a ring having 5-7 atoms; and wherein R⁷ isselected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; or a pharmaceutically-acceptablesalt thereof, thereby treating neuropathic pain in the subject.

Still other objects and advantages of the present disclosure will becomereadily apparent by those skilled in the art from the following detaileddescription, which is shown and described by reference to preferredaspects, simply by way of illustration of the best mode. As will berealized, the disclosure is capable of other and different aspects, andits several details are capable of modifications in various respects,without departing from the disclosure. Accordingly, the description isto be regarded as illustrative in nature and not as restrictive.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute apart of this specification and together with the description, serve toexplain the principles of the disclosure.

FIGS. 1A-C show the effects of boldine on locomotor functional recoveryof C57BL6 mice after moderate spinal cord injury (SCI) at the interspacebetween thoracic vertebrae T9 and T10. FIG. 1A shows Basso Mouse Scale(BMS) scores to examine open-field locomotor function after 5- and13-days post injury on sham, and vehicle or boldine treated animals.FIG. 1B shows a plot derived from the ladder rung walk test (LRWT),which describes the recovery of fine motor skills of mice, particularlythe number of missed foot placements, in percentage, when comparingvehicle to boldine treated SCI animals at 13 dpi. FIG. 1C shows atimeline of the studies performed.

FIGS. 2A-D show plots of mRNA levels of Cx43 (2A), NLRP3 (2B), ASC (2C),and caspase-1 (2D) in the hippocampus of sham mice and those havingcontusion spinal cord injury (SCI) with and without boldine treatment.mRNA levels in the hippocampus were determined by qPCR at 13 dpi usingtissues from mice that underwent laminectomy (Sham) or moderate (50kdyne) contusion SCI. ((*p<0.05 by one-way ANOVA, N=3 per group).

FIGS. 3A-B are plots showing that boldine normalizes spinal cord injury(SCI)-induced elevation of IL-1B mRNA levels in the thalamus. mRNAlevels were determined as described with reference to FIG. 2. (A) IL-1β;(B) CCL2. (*p<0.05 by ANOVA, N=3).

DETAILED DESCRIPTION

The present invention can be understood more readily by reference to thefollowing detailed description of the invention and the Examplesincluded therein.

Disclosed are components that can be used to perform the disclosedmethods and systems. These and other components are disclosed herein,and it is understood that when combinations, subsets, interactions,groups, etc. of these components are disclosed that while specificreference of each various individual and collective combinations andpermutation of these may not be explicitly disclosed, each isspecifically contemplated and described herein, for all methods andsystems. This applies to all aspects of this application including, butnot limited to, steps in disclosed methods. Thus, if there are a varietyof additional steps that can be performed it is understood that each ofthese additional steps can be performed with any specific embodiment orcombination of embodiments of the disclosed methods.

The present compositions, methods, and kits may be understood morereadily by reference to the following detailed description of preferredembodiments and the examples included therein.

While aspects of this disclosure can be described and claimed in aparticular statutory class, such as the system statutory class, this isfor convenience only and one of skill in the art will understand thateach aspect of this disclosure can be described and claimed in anystatutory class. Unless otherwise expressly stated, it is in no wayintended that any method or aspect set forth herein be construed asrequiring that its steps be performed in a specific order. Accordingly,where a method claim does not specifically state in the claims ordescription that the steps are to be limited to a specific order, it isno way intended that an order be inferred, in any respect. This holdsfor any possible non-express basis for interpretation, including mattersof logic with respect to arrangement of steps or operational flow, plainmeaning derived from grammatical organization or punctuation, or thenumber or type of aspects described in the specification.

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this pertains. The referencesdisclosed are also individually and specifically incorporated byreference herein for the material contained in them that is discussed inthe sentence in which the reference is relied upon. Nothing herein is tobe construed as an admission that the present application is notentitled to antedate such publication by virtue of prior invention.Further, stated publication dates may be different from actualpublication dates, which can require independent confirmation.

A. DEFINITIONS

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification, unless otherwise limited in specificinstances, either individually or as part of a larger group.

As used in the specification and in the claims, the term “comprising”can include the aspects “consisting of” and “consisting essentially of.”

As used in the specification and claims, the singular forms “a,” “an,”and “the” include plural referents unless the context clearly dictatesotherwise.

Ranges can be expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, another aspect includes from the one particular value and/orto the other particular value. Similarly, when values are expressed asapproximations, by use of the antecedent “about,” it will be understoodthat the particular value forms another aspect. It will be furtherunderstood that the endpoints of each of the ranges are significant bothin relation to the other endpoint, and independently of the otherendpoint. It is also understood that there are a number of valuesdisclosed herein, and that each value is also herein disclosed as“about” that particular value in addition to the value itself. Forexample, if the value “10” is disclosed, then “about 10” is alsodisclosed. It is also understood that each unit between two particularunits are also disclosed. For example, if 10 and 15 are disclosed, then11, 12, 13, and 14 are also disclosed.

As used herein, the terms “about” and “at or about” mean that the amountor value in question can be the value designated some other valueapproximately or about the same. It is generally understood, as usedherein, that it is the nominal value indicated ±10% variation unlessotherwise indicated or inferred. The term is intended to convey thatsimilar values promote equivalent results or effects recited in theclaims. That is, it is understood that amounts, sizes, formulations,parameters, and other quantities and characteristics are not and neednot be exact, but can be approximate and/or larger or smaller, asdesired, reflecting tolerances, conversion factors, rounding off,measurement error and the like, and other factors known to those ofskill in the art. In general, an amount, size, formulation, parameter orother quantity or characteristic is “about” or “approximate” whether ornot expressly stated to be such. It is understood that where “about” isused before a quantitative value, the parameter also includes thespecific quantitative value itself, unless specifically statedotherwise.

References in the specification and concluding claims to parts by weightof a particular element or component in a composition denotes the weightrelationship between the element or component and any other elements orcomponents in the composition or article for which a part by weight isexpressed. Thus, in a compound containing 2 parts by weight of componentX and 5 parts by weight component Y, X and Y are present at a weightratio of 2:5, and are present in such ratio regardless of whetheradditional components are contained in the compound.

A weight percent (wt. %) of a component, unless specifically stated tothe contrary, is based on the total weight of the formulation orcomposition in which the component is included.

As used herein, “IC₅₀” is intended to refer to the concentration of asubstance (e.g., a compound or a drug) that is required for 50%inhibition of a biological process, or component of a process, includinga protein, subunit, organelle, ribonucleoprotein, etc. In one aspect, anIC₅₀ can refer to the concentration of a substance that is required for50% inhibition in vivo, as further defined elsewhere herein. In afurther aspect, IC₅₀ refers to the half-maximal (50%) inhibitoryconcentration (IC) of a substance.

As used herein, “EC₅₀” is intended to refer to the concentration of asubstance (e.g., a compound or a drug) that is required for 50% agonismof a biological process, or component of a process, including a protein,subunit, organelle, ribonucleoprotein, etc. In one aspect, an EC₅₀ canrefer to the concentration of a substance that is required for 50%agonism in vivo, as further defined elsewhere herein. In a furtheraspect, EC₅₀ refers to the concentration of agonist that provokes aresponse halfway between the baseline and maximum response.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances where itdoes not.

The term “analog” as used herein refers to a chemical compound that isstructurally related to boldine. The analog can be prepared from boldineor other suitable starting materials, and thus the term “analog” doesnot necessarily imply that the compound was derived from or preparedfrom boldine.

The term “pharmaceutically acceptable salt,” as used herein, refers toan inorganic or organic salt of a disclosed compound that is suitablefor administration to a subject.

As used herein, the term “pharmaceutically acceptable carrier” refers tosterile aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, as well as sterile powders for reconstitution into sterileinjectable solutions or dispersions just prior to use. Examples ofsuitable aqueous and nonaqueous carriers, diluents, solvents or vehiclesinclude water, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol and the like), carboxymethylcellulose and suitablemixtures thereof, vegetable oils (such as olive oil) and injectableorganic esters such as ethyl oleate. Proper fluidity can be maintained,for example, by the use of coating materials such as lecithin, by themaintenance of the required particle size in the case of dispersions andby the use of surfactants. These compositions can also contain adjuvantssuch as preservatives, wetting agents, emulsifying agents and dispersingagents. Prevention of the action of microorganisms can be ensured by theinclusion of various antibacterial and antifungal agents such asparaben, chlorobutanol, phenol, sorbic acid and the like. It can also bedesirable to include isotonic agents such as sugars, sodium chloride andthe like. Prolonged absorption of the injectable pharmaceutical form canbe brought about by the inclusion of agents, such as aluminummonostearate and gelatin, which delay absorption. Injectable depot formsare made by forming microencapsule matrices of the drug in biodegradablepolymers such as polylactide-polyglycolide, poly(orthoesters) andpoly(anhydrides). Depending upon the ratio of drug to polymer and thenature of the particular polymer employed, the rate of drug release canbe controlled. Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues. The injectable formulations can be sterilized, forexample, by filtration through a bacterial-retaining filter or byincorporating sterilizing agents in the form of sterile solidcompositions which can be dissolved or dispersed in sterile water orother sterile injectable media just prior to use. Suitable inertcarriers can include sugars such as lactose. Desirably, at least 95% byweight of the particles of the active ingredient have an effectiveparticle size in the range of 0.01 to 10 micrometers.

As used herein, the term “by weight,” when used in conjunction with acomponent, unless specially stated to the contrary is based on the totalweight of the formulation or composition in which the component isincluded. For example, if a particular element or component in acomposition or article is said to have 8% by weight, it is understoodthat this percentage is in relation to a total compositional percentageof 100%.

A weight percent of a component, or weight %, or wt %, unlessspecifically stated to the contrary, is based on the total weight of theformulation or composition in which the component is included.

As used herein, the term “subject” can be a vertebrate, such as amammal, a fish, a bird, a reptile, or an amphibian. Thus, the subjectcan be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat,cow, cat, guinea pig or rodent. The term does not denote a particularage or sex. Thus, adult and newborn subjects, as well as fetuses,whether male or female, are intended to be covered. In one aspect, thesubject is a mammal. A patient refers to a subject afflicted with anailment, disease, or disorder. The term “patient” includes human andveterinary subjects.

As used herein, the terms “treatment” and “treating” refer to themedical management of a subject with the intent to cure, ameliorate,stabilize, or prevent an ailment, disease, pathological condition,disorder, or injury. This term includes active treatment, that is,treatment directed specifically toward the improvement of a disease,pathological condition, disorder, or injury, and also includes causaltreatment, that is, treatment directed toward removal of the cause ofthe associated disease, pathological condition, disorder, or injury. Inaddition, this term includes palliative treatment, that is, treatmentdesigned for the relief of symptoms rather than the curing of thedisease, pathological condition, disorder, or injury; preventativetreatment, that is, treatment directed to minimizing or partially orcompletely inhibiting the development of the associated disease,pathological condition, disorder, or injury; and supportive treatment,that is, treatment employed to supplement another specific therapydirected toward the improvement of the associated disease, pathologicalcondition, disorder, or injury. In various aspects, the term covers anytreatment of a subject, including a mammal (e.g., a human), andincludes: (i) preventing the disorder or condition from occurring in asubject that can be predisposed to the disorder or condition but has notyet been diagnosed as having it; (ii) inhibiting the disorder orcondition, i.e., arresting its development or exacerbation thereof; or(iii) relieving the disorder or condition, i.e., promoting healing ofthe disorder or condition. In one aspect, the subject is a mammal suchas a primate, and, in a further aspect, the subject is a human.

As used herein, the term “prevent” or “preventing” refers to precluding,averting, obviating, forestalling, stopping, or hindering something fromhappening, especially by advance action. It is understood that wherereduce, inhibit or prevent are used herein, unless specificallyindicated otherwise, the use of the other two words is also expresslydisclosed.

As used herein, the term “diagnosed” means having been subjected to aphysical examination by a person of skill, for example, a physician, andfound to have a condition that can be diagnosed or treated by adisclosed compound.

As used herein, the terms “administering” and “administration” refer toany method of providing a pharmaceutical preparation to a subject. Suchmethods are well known to those skilled in the art and include, but arenot limited to, oral administration, transdermal administration,administration by inhalation, nasal administration, topicaladministration, intravaginal administration, ophthalmic administration,intraaural administration, intracerebral administration, rectaladministration, sublingual administration, buccal administration, andparenteral administration, including injectable such as intravenousadministration, intra-arterial administration, intramuscularadministration, and subcutaneous administration. Administration can becontinuous or intermittent. In various aspects, a preparation can beadministered therapeutically; that is, administered to treat an existingdisease or condition. In further various aspects, a preparation can beadministered prophylactically; that is, administered for prevention of adisease or condition.

As used herein, the terms “effective amount” and “amount effective”refer to an amount that is sufficient to achieve the desired result orto have an effect on an undesired condition. For example, a“therapeutically effective amount” refers to an amount that issufficient to achieve the desired therapeutic result or to have aneffect on undesired symptoms, but is generally insufficient to causeadverse side effects. The specific therapeutically effective dose levelfor any particular patient will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;the specific composition employed; the age, body weight, general health,sex and diet of the patient; the time of administration; the route ofadministration; the rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed and like factors well known in themedical arts. For example, it is well within the skill of the art tostart doses of a compound at levels lower than those required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved. If desired, the effective dailydose can be divided into multiple doses for purposes of administration.Consequently, single dose compositions can contain such amounts orsubmultiples thereof to make up the daily dose. The dosage can beadjusted by the individual physician in the event of anycontraindications. Dosage can vary, and can be administered in one ormore dose administrations daily, for one or several days. Guidance canbe found in the literature for appropriate dosages for given classes ofpharmaceutical products. In further various aspects, a preparation canbe administered in a “prophylactically effective amount”; that is, anamount effective for prevention of a disease or condition.

The “central nervous system” (CNS) includes the brain, spinal cord,optic, olfactory, and auditory systems. The CNS comprises both neuronsand glial cells (neuroglia), which are support cells that aid thefunction of neurons. Oligodendrocytes, astrocytes, and microglia areglial cells within the CNS. Oligodendrocytes myelinate axons in the CNS,while astrocytes contribute to the blood-brain barrier, which separatesthe CNS from blood proteins and cells, and perform a number ofsupportive functions for neurons. Microglial cells serve immune systemfunctions.

The “peripheral nervous system” (PNS), for purposes of this disclosure,includes the cranial nerves arising from the brain (other than the opticand olfactory nerves), the spinal nerves arising from the spinal cord,sensory nerve cell bodies, and their processes, i.e., all nervous tissueoutside of the CNS. The PNS comprises both neurons and glial cells(neuroglia), which are support cells that aid the function of neurons.Glial cells within the PNS are known as Schwann cells, and serve tomyelinate axons by providing a sheath that surrounds the axons. Invarious aspects, the methods and compositions described herein can beapplied to different portions of the PNS.

The term “injury to the nervous system,” including the central orperipheral nervous system, refers to any injury to the nervous systemcaused by trauma instead of disease (e.g., a disease such as cancer).

The term “central nervous system injury” refers to any injury to thecentral nervous system caused by trauma instead of disease (e.g., adisease such as cancer). The term encompasses injuries to the centralnervous system that result in loss or impairment of motor function,sensory function, or a combination thereof.

As used herein, “traumatic brain injury” or “TBI” refers to an acquiredbrain injury or head injury in which trauma damages the brain. Thedamage can be localized, i.e., limited to one area of the brain, ordiffuse, affecting one or more areas of the brain.

The term “spinal cord injury,” as used herein, means any injury to thespinal cord that is caused by trauma instead of disease (e.g., a diseasesuch as cancer). Depending on where the spinal cord and nerve roots aredamaged, the symptoms can vary widely, for example from pain toparalysis to incontinence. Spinal cord injuries are described at variouslevels of “incomplete,” which can vary from having no effect on thesubject to a “complete” injury which means a total loss of function.Spinal cord injuries have many causes, but are typically associated withmajor trauma from motor vehicle accidents, falls, sports injuries, andviolence. The abbreviation “SCI” means spinal cord injury.

“Spinal cord contusion,” as used herein, refers to an injury caused bytrauma instead of disease in which part of the spinal cord is crushedwith part of its tissue spared, particularly the ventral nerve fibersconnecting the spinal cord rostral and caudal to the injury.

The term “peripheral nervous system injury,” as used herein, refers toany injury to a peripheral nerve caused by trauma instead of disease(e.g., a disease such as cancer). “Peripheral nerve injury” encompassesall degrees of nerve injury, including the lowest degree of nerve injuryin which the nerve remains intact but signaling ability is damaged,known as neurapraxia. The term also includes the second degree in whichthe axon is damaged but the surrounding connecting tissue remainsintact, known as axonotmesis. Finally, the term encompasses the lastdegree in which both the axon and connective tissue are damaged, knownas neurotmesis.

The term “nerve crush injury,” as used herein, refers to traumaticcompression of the nerve from a blunt object, such as a bat, surgicalclamp or other crushing object that does not result in a completetransection of the nerve.

The term “neuropathic pain,” as used herein, refers to chronic painresulting from injury to the nervous system caused by trauma instead ofdisease (e.g., a disease such as cancer or diabetes). The injuryresulting in neuropathic pain can be to the central nervous system(brain and spinal cord) or the peripheral nervous system (nerves outsidethe brain and spinal cord).

As used herein, “dosage form” means a pharmacologically active materialin a medium, carrier, vehicle, or device suitable for administration toa subject. A dosage forms can comprise inventive a disclosed compound, aproduct of a disclosed method of making, or a salt, solvate, orpolymorph thereof, in combination with a pharmaceutically acceptableexcipient, such as a preservative, buffer, saline, or phosphate bufferedsaline. Dosage forms can be made using conventional pharmaceuticalmanufacturing and compounding techniques. Dosage forms can compriseinorganic or organic buffers (e.g., sodium or potassium salts ofphosphate, carbonate, acetate, or citrate) and pH adjustment agents(e.g., hydrochloric acid, sodium or potassium hydroxide, salts ofcitrate or acetate, amino acids and their salts) antioxidants (e.g.,ascorbic acid, alpha-tocopherol), surfactants (e.g., polysorbate 20,polysorbate 80, polyoxyethylene9-10 nonyl phenol, sodium desoxycholate),solution and/or cryo/lyo stabilizers (e.g., sucrose, lactose, mannitol,trehalose), osmotic adjustment agents (e.g., salts or sugars),antibacterial agents (e.g., benzoic acid, phenol, gentamicin),antifoaming agents (e.g., polydimethylsilozone), preservatives (e.g.,thimerosal, 2-phenoxyethanol, EDTA), polymeric stabilizers andviscosity-adjustment agents (e.g., polyvinylpyrrolidone, poloxamer 488,carboxymethylcellulose) and co-solvents (e.g., glycerol, polyethyleneglycol, ethanol). A dosage form formulated for injectable use can have adisclosed compound, a product of a disclosed method of making, or asalt, solvate, or polymorph thereof, suspended in sterile salinesolution for injection together with a preservative.

As used herein, “kit” means a collection of at least two componentsconstituting the kit. Together, the components constitute a functionalunit for a given purpose. Individual member components may be physicallypackaged together or separately. For example, a kit comprising aninstruction for using the kit may or may not physically include theinstruction with other individual member components. Instead, theinstruction can be supplied as a separate member component, either in apaper form or an electronic form which may be supplied on computerreadable memory device or downloaded from an internet website, or as arecorded presentation.

As used herein, “instruction(s)” means documents describing relevantmaterials or methodologies pertaining to a kit. These materials mayinclude any combination of the following: background information, listof components and their availability information (purchase information,etc.), brief or detailed protocols for using the kit, trouble-shooting,references, technical support, and any other related documents.Instructions can be supplied with the kit or as a separate membercomponent, either as a paper form or an electronic form which may besupplied on computer readable memory device or downloaded from aninternet website, or as recorded presentation. Instructions can compriseone or multiple documents, and are meant to include future updates.

As used herein, the terms “therapeutic agent” include any synthetic ornaturally occurring biologically active compound or composition ofmatter which, when administered to an organism (human or nonhumananimal), induces a desired pharmacologic, immunogenic, and/orphysiologic effect by local and/or systemic action. The term thereforeencompasses those compounds or chemicals traditionally regarded asdrugs, vaccines, and biopharmaceuticals including molecules such asproteins, peptides, hormones, nucleic acids, gene constructs and thelike. Examples of therapeutic agents are described in well-knownliterature references such as the Merck Index (14^(th) edition), thePhysicians' Desk Reference (64^(th) edition), and The PharmacologicalBasis of Therapeutics (12^(th) edition), and they include, withoutlimitation, medicaments; vitamins; mineral supplements; substances usedfor the treatment, prevention, diagnosis, cure or mitigation of adisease or illness; substances that affect the structure or function ofthe body, or pro-drugs, which become biologically active or more activeafter they have been placed in a physiological environment. For example,the term “therapeutic agent” includes compounds or compositions for usein all of the major therapeutic areas including, but not limited to,adjuvants; anti-infectives such as antibiotics and antiviral agents;anti-cancer and anti-neoplastic agents such as kinase inhibitors, polyADP ribose polymerase (PARP) inhibitors and other DNA damage responsemodifiers, epigenetic agents such as bromodomain and extra-terminal(BET) inhibitors, histone deacetylase (HDAc) inhibitors, iron chelotorsand other ribonucleotides reductase inhibitors, proteasome inhibitorsand Nedd8-activating enzyme (NAE) inhibitors, mammalian target ofrapamycin (mTOR) inhibitors, traditional cytotoxic agents such aspaclitaxel, dox, irinotecan, and platinum compounds, immune checkpointblockade agents such as cytotoxic T lymphocyte antigen-4 (CTLA-4)monoclonal antibody (mAB), programmed cell death protein 1(PD-1)/programmed cell death-ligand 1 (PD-L1) mAB, cluster ofdifferentiation 47 (CD47) mAB, toll-like receptor (TLR) agonists andother immune modifiers, cell therapeutics such as chimeric antigenreceptor T-cell (CAR-T)/chimeric antigen receptor natural killer(CAR-NK) cells, and proteins such as interferons (IFNs), interleukins(ILs), and mAbs; anti-ALS agents such as entry inhibitors, fusioninhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs),nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reversetranscriptase inhibitors, NCP7 inhibitors, protease inhibitors, andintegrase inhibitors; analgesics and analgesic combinations, anorexics,anti-inflammatory agents, anti-epileptics, local and generalanesthetics, hypnotics, sedatives, antipsychotic agents, neurolepticagents, antidepressants, anxiolytics, antagonists, neuron blockingagents, anticholinergic and cholinomimetic agents, antimuscarinic andmuscarinic agents, antiadrenergics, antiarrhythmics, antihypertensiveagents, hormones, and nutrients, antiarthritics, antiasthmatic agents,anticonvulsants, antihistamines, antinauseants, antineoplastics,antipruritics, antipyretics; antispasmodics, cardiovascular preparations(including calcium channel blockers, beta-blockers, beta-agonists andantiarrythmics), antihypertensives, diuretics, vasodilators; centralnervous system stimulants; cough and cold preparations; decongestants;diagnostics; hormones; bone growth stimulants and bone resorptioninhibitors; immunosuppressives; muscle relaxants; psychostimulants;sedatives; tranquilizers; proteins, peptides, and fragments thereof(whether naturally occurring, chemically synthesized or recombinantlyproduced); and nucleic acid molecules (polymeric forms of two or morenucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA)including both double- and single-stranded molecules, gene constructs,expression vectors, antisense molecules and the like), small molecules(e.g., doxorubicin) and other biologically active macromolecules suchas, for example, proteins and enzymes. The agent may be a biologicallyactive agent used in medical, including veterinary, applications and inagriculture, such as with plants, as well as other areas. The term“therapeutic agent” also includes without limitation, medicaments;vitamins; mineral supplements; substances used for the treatment,prevention, diagnosis, cure or mitigation of disease or illness; orsubstances which affect the structure or function of the body; orpro-drugs, which become biologically active or more active after theyhave been placed in a predetermined physiological environment.

As used herein, the term “substantially,” in, for example, the context“substantially free of” refers to a composition having less than about10% by weight, e.g., less than about 5%, less than about 1%, less thanabout 0.5%, less than about 0.1%, less than about 0.05%, or less thanabout 0.01% by weight of the stated material, based on the total weightof the composition.

It is further understood that the term “substantially,” when used inreference to a composition, refers to at least about 60% by weight,e.g., at least about 65%, at least about 70%, at least about 75%, atleast about 80%, at least about 85%, at least about 90%, at least about91%, at least about 92%, at least about 93%, at least about 94%, atleast about 95%, at least about 96%, at least about 97%, at least about98%, at least about 99%, or about 100% by weight, based on the totalweight of the composition, of a specified feature, component, or acombination of the components. It is further understood that if thecomposition comprises more than one component, the two or morecomponents can be present in any ratio predetermined by one of ordinaryskill in the art.

As used herein, the term “derivative” refers to a compound having astructure similar to the structure of a certain compound (e.g., acompound disclosed herein) and whose structure is sufficiently similarto those disclosed herein and based upon that similarity, would beexpected by one skilled in the art to exhibit the same or similaractivities and utilities as the claimed compounds, or to induce, as aprecursor, the same or similar activities and utilities as the claimedcompounds. Exemplary derivatives include salts, esters, and amides,salts of esters or amides, and N-oxides of a parent compound.

As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, and aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,for example, those described below. The permissible substituents can beone or more and the same or different for appropriate organic compounds.For purposes of this disclosure, the heteroatoms, such as nitrogen, canhave hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valences of theheteroatoms. This disclosure is not intended to be limited in any mannerby the permissible substituents of organic compounds. Also, the terms“substitution” or “substituted with” include the implicit proviso thatsuch substitution is in accordance with permitted valence of thesubstituted atom and the substituent, and that the substitution resultsin a stable compound, e.g., a compound that does not spontaneouslyundergo transformation such as by rearrangement, cyclization,elimination, etc. It is also contemplated that, in certain aspects,unless expressly indicated to the contrary, individual substituents canbe further optionally substituted (i.e., further substituted orunsubstituted).

The term “aliphatic” or “aliphatic group,” as used herein, denotes ahydrocarbon moiety that may be straight chain (i.e., unbranched),branched, or cyclic (including fused, bridging, and spirofusedpolycyclic) and may be completely saturated or may contain one or moreunits of unsaturation, but which is not aromatic. Unless otherwisespecified, aliphatic groups contain 1-20 carbon atoms. Aliphatic groupsinclude, but are not limited to, linear or branched, alkyl, alkenyl, andalkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl,(cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term “alkyl” as used herein is a branched or unbranched saturatedhydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl,isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl,dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. Thealkyl group can be cyclic or acyclic. The alkyl group can be branched orunbranched. The alkyl group can also be substituted or unsubstituted.For example, the alkyl group can be substituted with one or more groupsincluding, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether,halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein.A “lower alkyl” group is an alkyl group containing from one to six(e.g., from one to four) carbon atoms. The term alkyl group can also bea C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the likeup to and including a C1-C24 alkyl.

Throughout the specification “alkyl” is generally used to refer to bothunsubstituted alkyl groups and substituted alkyl groups; however,substituted alkyl groups are also specifically referred to herein byidentifying the specific substituent(s) on the alkyl group. For example,the term “halogenated alkyl” or “haloalkyl” specifically refers to analkyl group that is substituted with one or more halide, e.g., fluorine,chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyl”specifically refers to an alkyl group that is substituted with a singlehalide, e.g. fluorine, chlorine, bromine, or iodine. The term“polyhaloalkyl” specifically refers to an alkyl group that isindependently substituted with two or more halides, i.e. each halidesubstituent need not be the same halide as another halide substituent,nor do the multiple instances of a halide substituent need to be on thesame carbon. The term “alkoxyalkyl” specifically refers to an alkylgroup that is substituted with one or more alkoxy groups, as describedbelow. The term “aminoalkyl” specifically refers to an alkyl group thatis substituted with one or more amino groups. The term “hydroxyalkyl”specifically refers to an alkyl group that is substituted with one ormore hydroxy groups. When “alkyl” is used in one instance and a specificterm such as “hydroxyalkyl” is used in another, it is not meant to implythat the term “alkyl” does not also refer to specific terms such as“hydroxyalkyl” and the like.

This practice is also used for other groups described. That is, while aterm such as “cycloalkyl” refers to both unsubstituted and substitutedcycloalkyl moieties, the substituted moieties can, in addition, bespecifically identified herein; for example, a particular substitutedcycloalkyl can be referred to as, e.g., an “alkylcycloalkyl.” Similarly,a substituted alkoxy can be specifically referred to as, e.g., a“halogenated alkoxy,” a particular substituted alkenyl can be, e.g., an“alkenylalcohol,” and the like. Again, the practice of using a generalterm, such as “cycloalkyl,” and a specific term, such as“alkylcycloalkyl,” is not meant to imply that the general term does notalso include the specific term.

The term “cycloalkyl” as used herein is a non-aromatic carbon-based ringcomposed of at least three carbon atoms. Examples of cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is anon-aromatic carbon-based ring type of cycloalkyl group as definedabove, and is included within the meaning of the term “cycloalkyl,”where at least one of the carbon atoms of the ring is replaced with aheteroatom such as, but not limited to, nitrogen, oxygen, sulfur, orphosphorus. The cycloalkyl group and heterocycloalkyl group can besubstituted or unsubstituted. The cycloalkyl group and heterocycloalkylgroup can be substituted with one or more groups including, but notlimited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy,nitro, silyl, sulfo-oxo, or thiol as described herein.

The term “polyalkylene group” as used herein is a group having two ormore CH₂ groups linked to one another. The polyalkylene group can berepresented by the formula —(CH₂)_(a)—, where “a” is an integer of from2 to 500.

The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl orcycloalkyl group bonded through an ether linkage; that is, an “alkoxy”group can be defined as —OA¹ where A¹ is alkyl or cycloalkyl as definedabove. “Alkoxy” also includes polymers of alkoxy groups as justdescribed; that is, an alkoxy can be a polyether such as —OA¹-OA² or—OA¹-(OA²)_(a)-OA³, where “a” is an integer of from 1 to 200 and A¹, A²,and A³ are alkyl and/or cycloalkyl groups.

The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24carbon atoms with a structural formula containing at least onecarbon-carbon double bond. Asymmetric structures such as (A¹A²)C═C(A³A⁴)are intended to include both the E and Z isomers. This can be presumedin structural formulae herein wherein an asymmetric alkene is present,or it can be explicitly indicated by the bond symbol C═C. The alkenylgroup can be substituted with one or more groups including, but notlimited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester,ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, orthiol, as described herein.

The term “cycloalkenyl” as used herein is a non-aromatic carbon-basedring composed of at least three carbon atoms and containing at least onecarbon-carbon double bound, i.e., C═C. Examples of cycloalkenyl groupsinclude, but are not limited to, cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl,norbornenyl, and the like. The term “heterocycloalkenyl” is a type ofcycloalkenyl group as defined above, and is included within the meaningof the term “cycloalkenyl,” where at least one of the carbon atoms ofthe ring is replaced with a heteroatom such as, but not limited to,nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group andheterocycloalkenyl group can be substituted or unsubstituted. Thecycloalkenyl group and heterocycloalkenyl group can be substituted withone or more groups including, but not limited to, alkyl, cycloalkyl,alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl,aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone,azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24carbon atoms with a structural formula containing at least onecarbon-carbon triple bond. The alkynyl group can be unsubstituted orsubstituted with one or more groups including, but not limited to,alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether,halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, asdescribed herein.

The term “cycloalkynyl” as used herein is a non-aromatic carbon-basedring composed of at least seven carbon atoms and containing at least onecarbon-carbon triple bound. Examples of cycloalkynyl groups include, butare not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and thelike. The term “heterocycloalkynyl” is a type of cycloalkenyl group asdefined above, and is included within the meaning of the term“cycloalkynyl,” where at least one of the carbon atoms of the ring isreplaced with a heteroatom such as, but not limited to, nitrogen,oxygen, sulfur, or phosphorus. The cycloalkynyl group andheterocycloalkynyl group can be substituted or unsubstituted. Thecycloalkynyl group and heterocycloalkynyl group can be substituted withone or more groups including, but not limited to, alkyl, cycloalkyl,alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl,aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone,azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

The term “aromatic group” as used herein refers to a ring structurehaving cyclic clouds of delocalized π electrons above and below theplane of the molecule, where the π clouds contain (4n+2) π electrons. Afurther discussion of aromaticity is found in Morrison and Boyd, OrganicChemistry, (5th Ed., 1987), Chapter 13, entitled “Aromaticity,” pages477-497, incorporated herein by reference. The term “aromatic group” isinclusive of both aryl and heteroaryl groups.

The term “aryl” as used herein is a group that contains any carbon-basedaromatic group including, but not limited to, benzene, naphthalene,phenyl, biphenyl, anthracene, and the like. The aryl group can besubstituted or unsubstituted. The aryl group can be substituted with oneor more groups including, but not limited to, alkyl, cycloalkyl, alkoxy,alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl,aldehyde, —NH₂, carboxylic acid, ester, ether, halide, hydroxy, ketone,azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term“biaryl” is a specific type of aryl group and is included in thedefinition of “aryl.” In addition, the aryl group can be a single ringstructure or comprise multiple ring structures that are either fusedring structures or attached via one or more bridging groups such as acarbon-carbon bond. For example, biaryl can be two aryl groups that arebound together via a fused ring structure, as in naphthalene, or areattached via one or more carbon-carbon bonds, as in biphenyl.

The term “aldehyde” as used herein is represented by the formula —C(O)H.Throughout this specification “C(O)” is a short hand notation for acarbonyl group, i.e., C═O.

The terms “amine” or “amino” as used herein are represented by theformula —NA¹A², where A¹ and A² can be, independently, hydrogen oralkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group as described herein. A specific example of amino is—NH₂.

The term “alkylamino” as used herein is represented by the formula—NH(-alkyl) where alkyl is a described herein. Representative examplesinclude, but are not limited to, methylamino group, ethylamino group,propylamino group, isopropylamino group, butylamino group, isobutylaminogroup, (sec-butyl)amino group, (tert-butyl)amino group, pentylaminogroup, isopentylamino group, (tert-pentyl)amino group, hexylamino group,and the like.

The term “dialkylamino” as used herein is represented by the formula—N(-alkyl)₂ where alkyl is a described herein. Representative examplesinclude, but are not limited to, dimethylamino group, diethylaminogroup, dipropylamino group, diisopropylamino group, dibutylamino group,diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)aminogroup, dipentylamino group, diisopentylamino group, di(tert-pentyl)aminogroup, dihexylamino group, N-ethyl-N-methylamino group,N-methyl-N-propylamino group, N-ethyl-N-propylamino group and the like.

The term “carboxylic acid” as used herein is represented by the formula—C(O)OH.

The term “ester” as used herein is represented by the formula —OC(O)A¹or —C(O)OA¹, where A¹ can be alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.The term “polyester” as used herein is represented by the formula-(A¹O(O)C-A²-C(O)O)_(a)— or -(A¹O(O)C-A²-OC(O))_(a)—, where A¹ and A²can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and“a” is an integer from 1 to 500. “Polyester” is as the term used todescribe a group that is produced by the reaction between a compoundhaving at least two carboxylic acid groups with a compound having atleast two hydroxyl groups.

The term “ether” as used herein is represented by the formula A¹OA²,where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group describedherein. The term “polyether” as used herein is represented by theformula -(A¹O-A²O)_(a)—, where A¹ and A² can be, independently, analkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group described herein and “a” is an integer of from 1 to500. Examples of polyether groups include polyethylene oxide,polypropylene oxide, and polybutylene oxide.

The terms “halo,” “halogen,” or “halide,” as used herein can be usedinterchangeably and refer to F, Cl, Br, or I.

The terms “pseudohalide,” “pseudohalogen,” or “pseudohalo,” as usedherein can be used interchangeably and refer to functional groups thatbehave substantially similar to halides. Such functional groups include,by way of example, cyano, thiocyanato, azido, trifluoromethyl,trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.

The term “heteroalkyl,” as used herein refers to an alkyl groupcontaining at least one heteroatom. Suitable heteroatoms include, butare not limited to, 0, N, Si, P and S, wherein the nitrogen, phosphorousand sulfur atoms are optionally oxidized, and the nitrogen heteroatom isoptionally quaternized. Heteroalkyls can be substituted as defined abovefor alkyl groups.

The term “heteroaryl,” as used herein refers to an aromatic group thathas at least one heteroatom incorporated within the ring of the aromaticgroup. Examples of heteroatoms include, but are not limited to,nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides,and dioxides are permissible heteroatom substitutions. The heteroarylgroup can be substituted or unsubstituted. The heteroaryl group can besubstituted with one or more groups including, but not limited to,alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl,sulfo-oxo, or thiol as described herein. Heteroaryl groups can bemonocyclic, or alternatively fused ring systems. Heteroaryl groupsinclude, but are not limited to, furyl, imidazolyl, pyrimidinyl,tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl,isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl,benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl,benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, andpyrazolopyrimidinyl. Further not limiting examples of heteroaryl groupsinclude, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl,benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl,imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl,benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, andpyrido[2,3-b]pyrazinyl.

The terms “heterocycle” or “heterocyclyl,” as used herein can be usedinterchangeably and refer to single and multi-cyclic aromatic ornon-aromatic ring systems in which at least one of the ring members isother than carbon. Thus, the term is inclusive of, but not limited to,“heterocycloalkyl,” “heteroaryl,” “bicyclic heterocycle,” and“polycyclic heterocycle.” Heterocycle includes pyridine, pyrimidine,furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole,thiazole, imidazole, oxazole, including, 1,2,3-oxadiazole,1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including,1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole,including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine,including 1,2,4-triazine and 1,3,5-triazine, tetrazine, including1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine,azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. Theterm heterocyclyl group can also be a C2 heterocyclyl, C2-C3heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like upto and including a C2-C18 heterocyclyl. For example, a C2 heterocyclylcomprises a group which has two carbon atoms and at least oneheteroatom, including, but not limited to, aziridinyl, diazetidinyl,dihydrodiazetyl, oxiranyl, thiiranyl, and the like. Alternatively, forexample, a C5 heterocyclyl comprises a group that has five carbon atomsand at least one heteroatom, including, but not limited to, piperidinyl,tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and thelike. It is understood that a heterocyclyl group may be bound eitherthrough a heteroatom in the ring, where chemically possible, or one ofcarbons comprising the heterocyclyl ring.

The term “bicyclic heterocycle” or “bicyclic heterocyclyl,” as usedherein refers to a ring system in which at least one of the ring membersis other than carbon. Bicyclic heterocyclyl encompasses ring systemswherein an aromatic ring is fused with another aromatic ring, or whereinan aromatic ring is fused with a non-aromatic ring. Bicyclicheterocyclyl encompasses ring systems wherein a benzene ring is fused toa 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms orwherein a pyridine ring is fused to a 5- or a 6-membered ring containing1, 2 or 3 ring heteroatoms. Bicyclic heterocyclic groups include, butare not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl,benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl,2,3-dihydro-1,4-benzodioxinyl, 3,4-dihydro-2H-chromenyl,1H-pyrazolo[4,3-c]pyridin-3-yl; 1H-pyrrolo[3,2-b]pyridin-3-yl; and1H-pyrazolo[3,2-b]pyridin-3-yl.

The term “heterocycloalkyl” as used herein refers to an aliphatic,partially unsaturated or fully saturated, 3- to 14-membered ring system,including single rings of 3 to 8 atoms and bi- and tricyclic ringsystems. The heterocycloalkyl ring-systems include one to fourheteroatoms independently selected from oxygen, nitrogen, and sulfur,wherein a nitrogen and sulfur heteroatom optionally can be oxidized anda nitrogen heteroatom optionally can be substituted. Representativeheterocycloalkyl groups include, but are not limited to, pyrrolidinyl,pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl,piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl,isothiazolidinyl, and tetrahydrofuryl.

The term “hydroxyl” or “hydroxyl” as used herein is represented by theformula —OH.

The term “ketone” as used herein is represented by the formula A¹C(O)A²,where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group asdescribed herein.

The term “azide” or “azido” as used herein is represented by the formula—N₃.

The term “nitro” as used herein is represented by the formula —NO₂.

The term “nitrile” or “cyano” as used herein is represented by theformula —CN.

The term “silyl” as used herein is represented by the formula —SiA¹A²A³,where A¹, A², and A³ can be, independently, hydrogen or an alkyl,cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group as described herein.

The term “sulfo-oxo” as used herein is represented by the formulas—S(O)A¹, S(O)₂A¹, —OS(O)₂A¹, or —OS(O)₂OA¹, where A¹ can be hydrogen oran alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,aryl, or heteroaryl group as described herein. Throughout thisspecification “S(O)” is a short hand notation for S═O. The term“sulfonyl” is used herein to refer to the sulfo-oxo group represented bythe formula —S(O)₂A¹, where A¹ can be hydrogen or an alkyl, cycloalkyl,alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl groupas described herein. The term “sulfone” as used herein is represented bythe formula A¹S(O)₂A², where A¹ and A² can be, independently, an alkyl,cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, orheteroaryl group as described herein. The term “sulfoxide” as usedherein is represented by the formula A'S(O)A², where A¹ and A² can be,independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, or heteroaryl group as described herein.

The term “thiol” as used herein is represented by the formula —SH.

“R¹,” “R²,” “R³,” “R^(n),” where n is an integer, as used herein can,independently, possess one or more of the groups listed above. Forexample, if R¹ is a straight chain alkyl group, one of the hydrogenatoms of the alkyl group can optionally be substituted with a hydroxylgroup, an alkoxy group, an alkyl group, a halide, and the like.Depending upon the groups that are selected, a first group can beincorporated within second group or, alternatively, the first group canbe pendant (i.e., attached) to the second group. For example, with thephrase “an alkyl group comprising an amino group,” the amino group canbe incorporated within the backbone of the alkyl group. Alternatively,the amino group can be attached to the backbone of the alkyl group. Thenature of the group(s) that is (are) selected will determine if thefirst group is embedded or attached to the second group.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogen of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. In is also contemplated that, in certain aspects,unless expressly indicated to the contrary, individual substituents canbe further optionally substituted (i.e., further substituted orunsubstituted).

The term “stable,” as used herein, refers to compounds that are notsubstantially altered when subjected to conditions to allow for theirproduction, detection, and, in certain aspects, their recovery,purification, and use for one or more of the purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which may besubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(∘); —CH═CHPh, which may be substituted with R^(∘);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(∘); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘);—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘)₂; —(CH₂)₀₋₄N(R^(∘)) C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘),—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)O SiR^(∘) ₃; —(CH₂)₀₋₄C(O)R^(∘);—OC(O)(CH₂)₀₋₄SR—, SC(S)SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘); —(CH₂)₀₋₄C(O)NR^(∘)₂; —C(S)NR^(∘))₂; —C(S)SR^(∘); —(CH₂)₀₋₄OC(O)NR^(∘) ₂;—C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘); —C(O)CH₂C(O)R^(∘);—C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘); —(CH₂)₀₋₄S(O)₂R^(∘);—(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘); —S(O)₂NR^(∘) ₂;—(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘))S(O)₂NR^(∘) ₂; —N(R^(∘))S(O)₂R^(∘);—N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘); —P(O)R^(∘) ₂; —OP(O)R^(∘)₂; —OP(O)(OR^(∘))₂; SiR^(∘) ₃; —(C₁₋₄ straight or branched alkylene)O—)N(R^(∘))₂; or —(C₁₋₄ straight or branched)alkylene)C(O)O—N(R^(∘))₂,wherein each R^(∘) may be substituted as defined below and isindependently hydrogen, C1 aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, —CH₂-(5-6membered heteroaryl ring), or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, or, notwithstanding the definitionabove, two independent occurrences of R^(∘), taken together with theirintervening atom(s), form a 3-12-membered saturated, partiallyunsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, which may besubstituted as defined below.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently halogen, —(CH₂)₁₋₂R^(├), -(haloR^(●)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●), —(CH₂)₀₋₂CH(OR^(●))₂; —O(haloR^(●)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(●), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●),—(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●),—(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃, —OSiR^(●) ₃, —C(O)SR^(●), —(C₁₋₄straight or branched alkylene)C(O)OR^(●), or —SSR^(●) wherein each R^(●)is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(∘) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN, —C(O)OH,—C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein each R^(●) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)R^(†); wherein each R^(†)is independently hydrogen, Cis aliphatic which may be substituted asdefined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN,—C(O)OH, —C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or NO₂, wherein eachR^(●) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

The term “leaving group” refers to an atom (or a group of atoms) withelectron withdrawing ability that can be displaced as a stable species,taking with it the bonding electrons. Examples of suitable leavinggroups include halides and sulfonate esters, including, but not limitedto, triflate, mesylate, tosylate, and brosylate.

The terms “hydrolysable group” and “hydrolysable moiety” refer to afunctional group capable of undergoing hydrolysis, e.g., under basic oracidic conditions. Examples of hydrolysable residues include, withoutlimitation, acid halides, activated carboxylic acids, and variousprotecting groups known in the art (see, for example, “Protective Groupsin Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience,1999).

The term “organic residue” defines a carbon-containing residue, i.e., aresidue comprising at least one carbon atom, and includes but is notlimited to the carbon-containing groups, residues, or radicals definedhereinabove. Organic residues can contain various heteroatoms, or bebonded to another molecule through a heteroatom, including oxygen,nitrogen, sulfur, phosphorus, or the like. Examples of organic residuesinclude but are not limited alkyl or substituted alkyls, alkoxy orsubstituted alkoxy, mono or di-substituted amino, amide groups, etc.Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15,carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbonatoms, or 1 to 4 carbon atoms. In a further aspect, an organic residuecan comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbonatoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

A very close synonym of the term “residue” is the term “radical,” whichas used in the specification and concluding claims, refers to afragment, group, or substructure of a molecule described herein,regardless of how the molecule is prepared. For example, a2,4-thiazolidinedione radical in a particular compound has thestructure:

regardless of whether thiazolidinedione is used to prepare the compound.In some embodiments the radical (for example an alkyl) can be furthermodified (i.e., substituted alkyl) by having bonded thereto one or more“substituent radicals.” The number of atoms in a given radical is notcritical to the present invention unless it is indicated to the contraryelsewhere herein.

“Organic radicals,” as the term is defined and used herein, contain oneor more carbon atoms. An organic radical can have, for example, 1-26carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms,1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organicradical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbonatoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organicradicals often have hydrogen bound to at least some of the carbon atomsof the organic radical. One example, of an organic radical thatcomprises no inorganic atoms is a 5,6,7,8-tetrahydro-2-naphthyl radical.In some embodiments, an organic radical can contain 1-10 inorganicheteroatoms bound thereto or therein, including halogens, oxygen,sulfur, nitrogen, phosphorus, and the like. Examples of organic radicalsinclude but are not limited to an alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, mono-substituted amino, di-substituted amino,acyloxy, cyano, carboxy, carboalkoxy, alkyl carboxamide, substitutedalkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide,alkyl sulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy,substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl,heteroaryl, heterocyclic, or substituted heterocyclic radicals, whereinthe terms are defined elsewhere herein. A few non-limiting examples oforganic radicals that include heteroatoms include alkoxy radicals,trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals andthe like.

Compounds described herein can contain one or more double bonds and,thus, potentially give rise to cis/trans (E/Z) isomers, as well as otherconformational isomers. Unless stated to the contrary, the inventionincludes all such possible isomers, as well as mixtures of such isomers.

Unless stated to the contrary, a formula with chemical bonds shown onlyas solid lines and not as wedges or dashed lines contemplates eachpossible isomer, e.g., each enantiomer and diastereomer, and a mixtureof isomers, such as a racemic or scalemic mixture. Compounds describedherein can contain one or more asymmetric centers and, thus, potentiallygive rise to diastereomers and optical isomers. Unless stated to thecontrary, the present invention includes all such possible diastereomersas well as their racemic mixtures, their substantially pure resolvedenantiomers, all possible geometric isomers, and pharmaceuticallyacceptable salts thereof. Mixtures of stereoisomers, as well as isolatedspecific stereoisomers, are also included. During the course of thesynthetic procedures used to prepare such compounds, or in usingracemization or epimerization procedures known to those skilled in theart, the products of such procedures can be a mixture of stereoisomers.

Many organic compounds exist in optically active forms having theability to rotate the plane of plane-polarized light. In describing anoptically active compound, the prefixes D and L or R and S are used todenote the absolute configuration of the molecule about its chiralcenter(s). The prefixes d and 1 or (+) and (−) are employed to designatethe sign of rotation of plane-polarized light by the compound, with (−)or meaning that the compound is levorotatory. A compound prefixed with(+) or d is dextrorotatory. For a given chemical structure, thesecompounds, called stereoisomers, are identical except that they arenon-superimposable mirror images of one another. A specific stereoisomercan also be referred to as an enantiomer, and a mixture of such isomersis often called an enantiomeric mixture. A 50:50 mixture of enantiomersis referred to as a racemic mixture. Many of the compounds describedherein can have one or more chiral centers and therefore can exist indifferent enantiomeric forms. If desired, a chiral carbon can bedesignated with an asterisk (*). When bonds to the chiral carbon aredepicted as straight lines in the disclosed formulas, it is understoodthat both the (R) and (S) configurations of the chiral carbon, and henceboth enantiomers and mixtures thereof, are embraced within the formula.As is used in the art, when it is desired to specify the absoluteconfiguration about a chiral carbon, one of the bonds to the chiralcarbon can be depicted as a wedge (bonds to atoms above the plane) andthe other can be depicted as a series or wedge of short parallel linesis (bonds to atoms below the plane). The Cahn-Ingold-Prelog system canbe used to assign the (R) or (S) configuration to a chiral carbon.

When the disclosed compounds contain one chiral center, the compoundsexist in two enantiomeric forms. Unless specifically stated to thecontrary, a disclosed compound includes both enantiomers and mixtures ofenantiomers, such as the specific 50:50 mixture referred to as a racemicmixture. The enantiomers can be resolved by methods known to thoseskilled in the art, such as formation of diastereoisomeric salts whichmay be separated, for example, by crystallization (see, CRC Handbook ofOptical Resolutions via Diastereomeric Salt Formation by David Kozma(CRC Press, 2001)); formation of diastereoisomeric derivatives orcomplexes which may be separated, for example, by crystallization,gas-liquid or liquid chromatography; selective reaction of oneenantiomer with an enantiomer-specific reagent, for example enzymaticesterification; or gas-liquid or liquid chromatography in a chiralenvironment, for example on a chiral support for example silica with abound chiral ligand or in the presence of a chiral solvent. It will beappreciated that where the desired enantiomer is converted into anotherchemical entity by one of the separation procedures described above, afurther step can liberate the desired enantiomeric form. Alternatively,specific enantiomers can be synthesized by asymmetric synthesis usingoptically active reagents, substrates, catalysts or solvents, or byconverting one enantiomer into the other by asymmetric transformation.

Designation of a specific absolute configuration at a chiral carbon in adisclosed compound is understood to mean that the designatedenantiomeric form of the compounds can be provided in enantiomericexcess (e.e.). Enantiomeric excess, as used herein, is the presence of aparticular enantiomer at greater than 50%, for example, greater than60%, greater than 70%, greater than 75%, greater than 80%, greater than85%, greater than 90%, greater than 95%, greater than 98%, or greaterthan 99%. In one aspect, the designated enantiomer is substantially freefrom the other enantiomer. For example, the “R” forms of the compoundscan be substantially free from the “S” forms of the compounds and are,thus, in enantiomeric excess of the “S” forms. Conversely, “S” forms ofthe compounds can be substantially free of “R” forms of the compoundsand are, thus, in enantiomeric excess of the “R” forms.

When a disclosed compound has two or more chiral carbons, it can havemore than two optical isomers and can exist in diastereoisomeric forms.For example, when there are two chiral carbons, the compound can have upto four optical isomers and two pairs of enantiomers ((S,S)/(R,R) and(R,S)/(S,R)). The pairs of enantiomers (e.g., (S,S)/(R,R)) are mirrorimage stereoisomers of one another. The stereoisomers that are notmirror-images (e.g., (S,S) and (R,S)) are diastereomers. Thediastereoisomeric pairs can be separated by methods known to thoseskilled in the art, for example chromatography or crystallization andthe individual enantiomers within each pair may be separated asdescribed above. Unless otherwise specifically excluded, a disclosedcompound includes each diastereoisomer of such compounds and mixturesthereof.

The compounds according to this disclosure may form prodrugs at hydroxylor amino functionalities using alkoxy, amino acids, etc., groups as theprodrug forming moieties. For instance, the hydroxymethyl position mayform mono-, di- or triphosphates and again these phosphates can formprodrugs. Preparations of such prodrug derivatives are discussed invarious literature sources (examples are: Alexander et al., J. Med.Chem. 1988, 31, 318; Aligas-Martin et al., PCT WO 2000/041531, p. 30).The nitrogen function converted in preparing these derivatives is one(or more) of the nitrogen atoms of a compound of the disclosure.

“Derivatives” of the compounds disclosed herein are pharmaceuticallyacceptable salts, prodrugs, deuterated forms, radioactively labeledforms, isomers, solvates and combinations thereof. The “combinations”mentioned in this context are refer to derivatives falling within atleast two of the groups: pharmaceutically acceptable salts, prodrugs,deuterated forms, radioactively labeled forms, isomers, and solvates.Examples of radioactively labeled forms include compounds labeled withtritium, phosphorous-32, iodine-129, carbon-11, fluorine-18, and thelike.

Compounds described herein comprise atoms in both their natural isotopicabundance and in non-natural abundance. The disclosed compounds can beisotopically labeled or isotopically substituted compounds identical tothose described, but for the fact that one or more atoms are replaced byan atom having an atomic mass or mass number different from the atomicmass or mass number typically found in nature. Examples of isotopes thatcan be incorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F and ³⁶Cl,respectively. Compounds further comprise prodrugs thereof, andpharmaceutically acceptable salts of said compounds or of said prodrugswhich contain the aforementioned isotopes and/or other isotopes of otheratoms are within the scope of this invention. Certain isotopicallylabeled compounds of the present invention, for example those into whichradioactive isotopes such as ³H and ¹⁴C are incorporated, are useful indrug and/or substrate tissue distribution assays. Tritiated, i.e., ³H,and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for theirease of preparation and detectability. Further, substitution withheavier isotopes such as deuterium, i.e., ²H, can afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements and,hence, may be preferred in some circumstances. Isotopically labeledcompounds of the present invention and prodrugs thereof can generally beprepared by carrying out the procedures below, by substituting a readilyavailable isotopically labeled reagent for a non-isotopically labeledreagent.

The compounds described in the invention can be present as a solvate. Insome cases, the solvent used to prepare the solvate is an aqueoussolution, and the solvate is then often referred to as a hydrate. Thecompounds can be present as a hydrate, which can be obtained, forexample, by crystallization from a solvent or from aqueous solution. Inthis connection, one, two, three or any arbitrary number of solvent orwater molecules can combine with the compounds according to theinvention to form solvates and hydrates. Unless stated to the contrary,the invention includes all such possible solvates.

The term “co-crystal” means a physical association of two or moremolecules that owe their stability through non-covalent interaction. Oneor more components of this molecular complex provide a stable frameworkin the crystalline lattice. In certain instances, the guest moleculesare incorporated in the crystalline lattice as anhydrates or solvates,see e.g. “Crystal Engineering of the Composition of PharmaceuticalPhases. Do Pharmaceutical Co-crystals Represent a New Path to ImprovedMedicines?” Almarasson, O., et. al., The Royal Society of Chemistry,1889-1896, 2004. Examples of co-crystals include p-toluenesulfonic acidand benzenesulfonic acid.

It is also appreciated that certain compounds described herein can bepresent as an equilibrium of tautomers. For example, ketones with anα-hydrogen can exist in an equilibrium of the keto form and the enolform.

Likewise, amides with an N-hydrogen can exist in an equilibrium of theamide form and the imidic acid form. As another example, pyrazoles canexist in two tautomeric forms, N¹-unsubstituted, 3-A³ andN¹-unsubstituted, 5-A³ as shown below.

Unless stated to the contrary, the invention includes all such possibletautomers.

It is known that chemical substances form solids that are present indifferent states of order that are termed polymorphic forms ormodifications. The different modifications of a polymorphic substancecan differ greatly in their physical properties. The compounds accordingto the invention can be present in different polymorphic forms, with itbeing possible for particular modifications to be metastable. Unlessstated to the contrary, the invention includes all such possiblepolymorphic forms.

In some aspects, a structure of a compound can be represented by aformula:

which is understood to be equivalent to a formula:

wherein n is typically an integer. That is, R^(n) is understood torepresent five independent substituents, R^(n(a)), R^(n(b)), R^(n(c)),R^(n(d)), R^(n(e)). By “independent substituents,” it is meant that eachR substituent can be independently defined. For example, if in oneinstance R^(n(a)) is halogen, then R^(n(b)) is not necessarily halogenin that instance.

Certain materials, compounds, compositions, and components disclosedherein can be obtained commercially or readily synthesized usingtechniques generally known to those of skill in the art. For example,the starting materials and reagents used in preparing the disclosedcompounds and compositions are either available from commercialsuppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), AcrosOrganics (Morris Plains, N.J.), Strem Chemicals (Newburyport, Mass.),Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or areprepared by methods known to those skilled in the art followingprocedures set forth in references such as Fieser and Fieser's Reagentsfor Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd'sChemistry of Carbon Compounds, Volumes 1-5 and supplemental volumes(Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40(John Wiley and Sons, 1991); March's Advanced Organic Chemistry, (JohnWiley and Sons, 4th Edition); and Larock's Comprehensive OrganicTransformations (VCH Publishers Inc., 1989).

Unless otherwise expressly stated, it is in no way intended that anymethod set forth herein be construed as requiring that its steps beperformed in a specific order. Accordingly, where a method claim doesnot actually recite an order to be followed by its steps or it is nototherwise specifically stated in the claims or descriptions that thesteps are to be limited to a specific order, it is in no way intendedthat an order be inferred, in any respect. This holds for any possiblenon-express basis for interpretation, including: matters of logic withrespect to arrangement of steps or operational flow; plain meaningderived from grammatical organization or punctuation; the number or typeof embodiments described in the specification.

B. METHODS OF TREATING NERVOUS SYSTEM INJURY IN A SUBJECT

In one aspect, disclosed is a method of treating an injury to thenervous system in a subject, comprising administering to the subject aneffective amount of disclosed compound or a pharmaceutically-acceptablethereof, as further described below, to effectively treat the injury tothe nervous system in the subject. Without wishing to be bound by anytheory, the described compounds can be non-peptide,therapeutically-active compounds that block Cx43 HC selectively, therebytreating Cx43 mediated effects following a traumatic injury to thenervous system.

1. Compounds

In one aspect, the compounds useful for treating an injury to thenervous system in a subject are represented by the following formula:

wherein R¹ is selected from hydrogen and C1-C4 alkyl; wherein R² isselected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; wherein each of R³ and R⁴ isindependently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl; or wherein R³ and R⁴ join together to form a ring having 5-7atoms; wherein each of R⁵ and R⁶ is independently selected fromhydrogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; or wherein R⁵ and R⁶join together to form a ring having 5-7 atoms; and wherein R⁷ isselected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; or a pharmaceutically-acceptablesalt thereof.

In one aspect, R¹ is selected from hydrogen and methyl, ethyl, n-propyl,isopropyl, ethenyl, n-propenyl, isopropenyl, —CH₂F, —CH₂Cl, —CH₂CH₂F,—CH₂CH₂Cl, —CH₂CH₂CH₂F, —CH₂CH₂CH₂Cl, —CH(CH₃)CH₂F, —CH(CH₃)CH₂Cl,—CH₂CN, —CH₂CH₂CN, —CH₂CH₂CH₂CN, —CH(CH₃)CH₂CN, —CH₂OH, —CH₂CH₂OH,—CH₂CH₂CH₂OH, —CH(CH₃)CH₂OH, —CH₂NH₂, —CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂, and—CH(CH₃)CH₂NH₂.

In a further aspect, each of R² and R⁷ is independently selected fromhydrogen, —F, —Cl, —Br, —I, —CN, —NH₂, —OH, —NO₂, methyl, ethyl,n-propyl, isopropyl, ethenyl, n-propenyl, isopropenyl, —CH₂F, —CH₂Cl,—CH₂CH₂F, —CH₂CH₂Cl, —CH₂CH₂CH₂F, —CH₂CH₂CH₂Cl, —CH(CH₃)CH₂F,—CH(CH₃)CH₂Cl, —CH₂CN, —CH₂CH₂CN, —CH₂CH₂CH₂CN, —CH(CH₃)CH₂CN, —CH₂OH,—CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH(CH₃)CH₂OH, —OCF₃, —OCH₂CF₃, —OCH₂CH₂CF₃,—OCH(CH₃)CF₃, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃, —NHCH₃,—NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂,—N(CH₂CH₂CH₃)₂, —N(CH(CH₃)CH₃)₂, —N(CH₃)(CH₂CH₃), —CH₂NH₂, —CH₂CH₂NH₂,—CH₂CH₂CH₂NH₂, and —CH(CH₃)CH₂NH₂.

In a still further aspect, each of R³, R⁴, R⁵, and R⁶ is independentlyselected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. Ina still further aspect, each of R³, R⁴, R⁵, and R⁶ is independentlyselected from hydrogen, methyl, ethyl, n-propyl, isopropyl, ethenyl,n-propenyl, isopropenyl, —CH₂F, —CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl,—CH₂CH₂CH₂F, —CH₂CH₂CH₂Cl, —CH(CH₃)CH₂F, —CH(CH₃)CH₂Cl, —CH₂CN,—CH₂CH₂CN, —CH₂CH₂CH₂CN, —CH(CH₃)CH₂CN, —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH,—CH(CH₃)CH₂OH, —OCF₃, —OCH₂CF₃, —OCH₂CH₂CF₃, —OCH(CH₃)CF₃, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃, —NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃,—NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, —N(CH₂CH₂CH₃)₂, —N(CH(CH₃)CH₃)₂,—N(CH₃)(CH₂CH₃), —CH₂NH₂, —CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂, and —CH(CH₃)CH₂NH₂.

In another aspect, R³ and R⁴ and/or R⁵ and R⁶ can join together to forma ring having 5-7 atoms. Thus, for example, the compound can berepresented by the formula:

wherein each n and m is independently an integer ranging from 1-3; eachof R⁸ and R⁹ is independently selected from hydrogen, halogen, —CN,—NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In afurther aspect, each of R⁸ and R⁹ is independently selected fromhydrogen, —F, —Cl, —Br, —I, —CN, —NH₂, —OH, —NO₂, methyl, ethyl,n-propyl, isopropyl, ethenyl, n-propenyl, isopropenyl, —CH₂F, —CH₂Cl,—CH₂CH₂F, —CH₂CH₂Cl, —CH₂CH₂CH₂F, —CH₂CH₂CH₂Cl, —CH(CH₃)CH₂F,—CH(CH₃)CH₂Cl, —CH₂CN, —CH₂CH₂CN, —CH₂CH₂CH₂CN, —CH(CH₃)CH₂CN, —CH₂OH,—CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH(CH₃)CH₂OH, —OCH₂CF₃, —OCH₂CH₂CF₃,—OCH(CH₃)CF₃, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃, —NHCH₃,—NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂,—N(CH₂CH₂CH₃)₂, —N(CH(CH₃)CH₃)₂, —N(CH₃)(CH₂CH₃), —CH₂NH₂, —CH₂CH₂NH₂,—CH₂CH₂CH₂NH₂, and —CH(CH₃)CH₂NH₂.

In one aspect, each of R¹, R⁴, and R⁵ is independently selected fromhydrogen, methyl, ethyl, and propyl; each of R² and R⁷ is independentlyselected from hydrogen and halogen; and each of R³ and R⁶ is hydrogen.

In a further aspect, each of R¹, R⁴, and R⁵ is methyl; each of R² and R⁷is independently selected from hydrogen and halogen; and each of R³ andR⁶ is hydrogen.

In a still further aspect, each of R¹, R⁴, and R⁵ is independentlyselected from hydrogen, methyl, ethyl, and propyl; and each of R², R³,R⁶, and R⁷ is hydrogen.

Non-limiting examples of compounds having hydrogen or C1-C4substitutions at R¹ include the following. The C1-C4 substituents at R¹,when present, can be optionally substituted as described above.

Non-limiting examples of compounds having substitutions at R² and/or R⁷include the following:

Non-limiting examples of compounds having a halogen at R² and/or R⁷include the following:

Non-limiting examples of compounds substituted at R³-R⁶ include thefollowing:

According to one aspect, the compound is represented by the formula:

The compound shown above corresponds to a racemic mixture of boldine.Boldine is a naturally-occurring alkaloid present in the leaves and barkof Boldo (Peumus boldus Molina), a tree native to the central region ofChile, among other plants.

In various aspects, the compounds have at least one chiral center andcan be substantially free of other isomers (e.g., as a pure orsubstantially pure optical isomer having a specified activity), or maybe admixed, for example, with racemates or other stereoisomers. In oneaspect, the compound can be substantially enantiomerically pure. Forexample, the S enantiomer of boldine can be substantially free of orseparated from the R enantiomer of boldine. Similarly, for example, theR enantiomer of boldine can be substantially free of or separated fromthe S enantiomer of boldine. In one aspect, the compound can be about80% enantiomerically pure, about 85% enantiomerically pure, about 90%enantiomerically pure, about 91% enantiomerically pure, about 92%enantiomerically pure, about 93% enantiomerically pure, about 94%enantiomerically pure, about 95% enantiomerically pure, about 96%enantiomerically pure, about 97% enantiomerically pure, about 98%enantiomerically pure, about 99% enantiomerically pure, or about 100%enantiomerically pure.

In one exemplary aspect, the compound is represented by the followingformula:

The compound shown above is the S enantiomer of boldine (also known bythe IUPAC name,(S)-1,10-dimethoxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2,9-diol).S-boldine, when present, can be substantially free of other isomers(e.g., as a pure or substantially pure optical isomer having a specifiedactivity), or may be admixed, for example, with racemates or otherstereoisomers. In one aspect, S-boldine, when present, can be about 80%enantiomerically pure, about 85% enantiomerically pure, about 90%enantiomerically pure, about 91% enantiomerically pure, about 92%enantiomerically pure, about 93% enantiomerically pure, about 94%enantiomerically pure, about 95% enantiomerically pure, about 96%enantiomerically pure, about 97% enantiomerically pure, about 98%enantiomerically pure, about 99% enantiomerically pure, or about 100%enantiomerically pure.

The compounds can be administered to a subject as apharmaceutically-acceptable salt. Non-limiting examples ofpharmaceutically-acceptable salts are mineral acid (hydrochloric acid,hydrobromic acid, phosphoric acid, and the like) salts, organic acid(acetic acid, propionic acid, glutamic acid, citric acid and the like)salts, and quaternary ammonium (methyl iodide, ethyl iodide, and thelike) salts. Other non-limiting examples include, but are not limited,to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide,nitrate, bisulfate, phosphate, acid phosphate, phosphonic acid,isonicotinate, lactate, salicylate, citrate, tartrate, oleate, tannate,pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate,fumarate, gluconate, glucaronate, saccharate, formate, benzoate,glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate, and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Still other saltsinclude, but are not limited to, salts with inorganic bases includingalkali metal salts such as sodium salts, and potassium salts; alkalineearth metal salts such as calcium salts, and magnesium salts; aluminumsalts; and ammonium salts. Other salts with organic bases include saltswith diethylamine, diethanolamine, meglumine, andN,N′-dibenzylethylenediamine. It is understood that the pharmaceuticallyacceptable salts are non-toxic. Additional information on suitablepharmaceutically acceptable salts can be found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, which is incorporated herein by reference.

Pharmaceutically-acceptable salts of the compounds can be salts formedwith bases, namely cationic salts such as alkali and alkaline earthmetal salts, such as sodium, lithium, potassium, calcium, magnesium, aswell as ammonium salts, such as ammonium, trimethyl-ammonium,diethylammonium, and tris-(hydroxymethyl)-methyl-ammonium salts.Similarly, acid addition salts, such as mineral acids, organiccarboxylic and organic sulfonic acids, e.g., hydrochloric acid,methanesulfonic acid, maleic acid, are also contemplated. Neutral formsof boldine and its analogs can be regenerated by contacting the saltwith a base or acid and isolating the parent compound in a conventionalmanner.

In one aspect, the compound used for treating an injury to the nervoussystem in a subject is S-boldine hydrochloride. S-boldine hydrochloridecan be prepared from Boldo's bark, as described in A. Urzúa and P.Acuña, “Alkaloids from the bar of Peumus boldus,” Fitoterapia, vol. 54,no. 4, pp. 175-177, 1983, which is incorporated herein by reference.

2. Methods of Making the Compounds

In some aspects, the compounds can be obtained from a natural source,e.g., a plant or component thereof that naturally produces certainalkaloids such as those described herein. In a further aspect, thecompounds can be prepared according to the oxidative coupling reactionshown in Scheme 1.

Precursor compounds (1) can be dissolved in a suitable solvent such asethanol, water, or a combination thereof, and subjected to oxidativecoupling using a strong Lewis acid such as ferric chloride (FeCl₃) witha suitable acid such as hydrochloric acid. Following the couplingreaction, the resulting salts (2) can be converted to the neutralcompounds (3) if desired using a suitable base.

In a further aspect, an oxidative coupling reaction can be used oncompounds (4), which have at least one unsubstituted phenolic functionalgroup. Salts (5) can be reduced to neutral form (6) using a suitablebase. The unsubstituted phenolic groups can be further substituted asdesired.

According to one aspect, compounds (6) can be further substituted at oneor more phenolic hydroxyl groups according to Scheme 2. A suitablequaternary ammonium salt such as 7 shown below can be dissolved in asuitable solvent such as methanol with a suitable base such as potassiumhydroxide to give the corresponding substituted compounds (8).

According to one aspect, compounds in which R³ and R⁴ and/or R⁵ and R⁶join together to form a ring having 5-7 atoms can be prepared accordingto methods known in the art. In one aspect, such compounds can beprepared by nucleophilic substitution reactions such as the one shownbelow in Scheme 3.

In general, the reaction shown in Scheme 3 can be accomplished with asuitable weak base such as potassium carbonate, with the addition ofpotassium iodide, in a suitable solvent such as dimethylformamide.According to one aspect, the reaction shown above can be carried out ata suitable temperature, e.g., 105-120° C., for a suitable time, e.g.,1-12 hours. Other methods of preparing compounds in which R³ and R⁴and/or R⁵ and R⁶ join together to form a ring having 5-7 atoms will berecognized by those skilled in the art.

In a further aspect, compounds with halogen substitutions at R² and/orR⁷ can be prepared according to methods known in the art, such as theexemplary reaction Scheme 4.

Compounds of type (12) can be substituted with bromine, for example,using trifluoroacetic acid and a suitable reagent such asN-Bromosuccinimide for a suitable time such as 1-3 hours at roomtemperature to give compounds of type (13). Scheme 4 can be tailored asone of skill will appreciate to prepare various halogen substitutionpatterns on the aromatic rings.

3. Pharmaceutically-Acceptable Carriers and Dosage Forms

In various aspects, the compounds can be administered to a subject as acomposition or formulation comprising a pharmaceutically-acceptablecarrier. Non-limiting examples of suitable aqueous and nonaqueouscarriers, diluents, solvents or vehicles include water, ethanol, polyols(such as glycerol, propylene glycol, polyethylene glycol and the like),carboxymethylcellulose and suitable mixtures thereof, vegetable oils(such as olive oil) and injectable organic esters such as ethyl oleate.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions and by the use of surfactants.

Pharmaceutically-acceptable carries can also comprise adjuvants such aspreservatives, wetting agents, emulsifying agents and dispersing agents.Prevention of the action of microorganisms can be ensured by theinclusion of various antibacterial and antifungal agents such asparaben, chlorobutanol, phenol, sorbic acid and the like. It can also bedesirable to include isotonic agents such as sugars, sodium chloride andthe like. Prolonged absorption of the injectable pharmaceutical form canbe brought about by the inclusion of agents, such as aluminummonostearate and gelatin, which delay absorption. Injectable depot formscan be made by forming microencapsule matrices of the compounds inbiodegradable polymers such as polylactide-polyglycolide,poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drugto polymer and the nature of the particular polymer employed, the rateof drug release can be controlled. Depot injectable formulations canalso be prepared by entrapping the drug in liposomes or microemulsionswhich are compatible with body tissues. The injectable formulations canbe sterilized, for example, by filtration through a bacterial-retainingfilter or by incorporating sterilizing agents in the form of sterilesolid compositions which can be dissolved or dispersed in sterile wateror other sterile injectable media just prior to use. Suitable inertcarriers can include sugars such as lactose.

In some aspects, the pharmaceutically-acceptable carrier can include anexcipient. Suitable excipients include, without limitation, saccharides,for example, glucose, lactose, or sucrose, mannitol, or sorbitol,cellulose derivatives, and/or calcium phosphate, for example, tricalciumphosphate or acidic calcium phosphate.

In further aspects, the pharmaceutically-acceptable carrier can includea binder. Suitable binders include, without limitation, tare compoundssuch as starch paste, for example, corn, wheat, rice, and potato starch,gelatin, tragacanth, methylcellulose, hydroxypropyl methylcellulose,carboxymethylcellulose, and/or polyvinylpyrrolidone. In still furtheraspects, there can be a disintegrating agent, such as the aforementionedstarches and carboxymethyl starch, crosslinked polyvinylpyrrolidone,agar, or alginic acid or a salt thereof, such as sodium alginate.

In some aspects, the pharmaceutically-acceptable carrier can include anadditive. Examples of additives include, but are not limited to,diluents, buffers, binders, surface-active agents, lubricants,humectants, pH adjusting agents, preservatives (includinganti-oxidants), emulsifiers, occlusive agents, opacifiers, antioxidants,colorants, flavoring agents, gelling agents, thickening agents,stabilizers, and surfactants, among others. Thus, in various furtheraspects, the additive is vitamin E, gum acacia, citric acid, steviaextract powder, Luo Han Gou, Monoammonium Glycyrhizinate, AmmoniumGlycyrrhizinate, honey, or combinations thereof. In a still furtheraspect, the additive is a flavoring agent, a binder, a disintegrant, abulking agent, or silica. In a further aspect, the additive can includeflowability-control agents and lubricants, such as silicon dioxide,talc, stearic acid and salts thereof, such as magnesium stearate orcalcium stearate, and/or propylene glycol.

In various aspects, when the compounds are formulated for oral use, suchas for example, a tablet, pill, or capsule, the composition can includea coating layer that is resistant to gastric acid. Such a layer, invarious aspects, can include a concentrated solution of saccharides thatcan comprise gum arabic, talc, polyvinylpyrrolidone, polyethyleneglycol, and/or titanium dioxide, and suitable organic solvents or saltsthereof.

Dosage forms can comprise the compounds or a pharmaceutically-acceptablesalt thereof, together in combination with a pharmaceutically acceptableexcipient, such as a preservative, buffer, saline, or phosphate bufferedsaline. Dosage forms can be made using conventional pharmaceuticalmanufacturing and compounding techniques. Dosage forms can compriseinorganic or organic buffers (e.g., sodium or potassium salts ofphosphate, carbonate, acetate, or citrate) and pH adjustment agents(e.g., hydrochloric acid, sodium or potassium hydroxide, salts ofcitrate or acetate, amino acids and their salts) antioxidants (e.g.,ascorbic acid, alpha-tocopherol), surfactants (e.g., polysorbate 20,polysorbate 80, polyoxyethylene9-10 nonyl phenol, sodium desoxycholate),solution and/or cryo/lyo stabilizers (e.g., sucrose, lactose, mannitol,trehalose), osmotic adjustment agents (e.g., salts or sugars),antibacterial agents (e.g., benzoic acid, phenol, gentamicin),antifoaming agents (e.g., polydimethylsilozone), preservatives (e.g.,thimerosal, 2-phenoxyethanol, EDTA), polymeric stabilizers andviscosity-adjustment agents (e.g., polyvinylpyrrolidone, poloxamer 488,carboxymethylcellulose) and co-solvents (e.g., glycerol, polyethyleneglycol, ethanol). A dosage form formulated for injectable use can have adisclosed composition or a product of a disclosed method of making,suspended in sterile saline solution for injection together with apreservative.

4. Treatment Methods

In one aspect, the compounds can be administered to a subject having aninjury to the nervous system. According to one aspect, the injury to thenervous system is a central nervous system injury or a peripheralnervous system injury. In a further aspect, the injury to the nervoussystem is a spinal cord injury (SCI), spinal cord contusion, nerve crushinjury, or traumatic brain injury (TBI). In a still further aspect, asymptom of the injury to the nervous system is neuropathic pain, loss ofvoluntary muscle control, loss of locomotor function, or a combinationthereof.

In some aspects, the compounds, when administered to the subject in atherapeutically effective amount, can be sufficient to cause adetectable improvement in, or a reduction in the progression of, one ormore of the following symptoms of the injury to the nervous system:neuropathic pain, loss of neuroplasticity, loss of voluntary musclecontrol, loss or impairment of locomotor function, loss or impairment ofsensory function, or a combination thereof.

For example, when the injury to the nervous system is a spinal cordinjury (SCI), the compounds can improve nervous system dysfunctioncaused by trauma to the cervical, thoracic, lumbar or sacral segments ofthe spinal cord, including without limitation dysfunction caused bytrauma to one or more of dermatomes C1, C2, C3, C4, C5, C6, C7, T1, T2,T3, T4, T5, T6, T7, T8, T9, T10, T11, T12, L1, L2, L3, L4 or L5.

Similarly, in some aspects, the compounds can improve nervous systemdysfunction resulting from traumatic brain injury (TBI). In variousaspects, the TBI can be an injury to the frontal lobe, parietal lobe,occipital lobe, temporal lobe, brain stem, or cerebellum. In someaspects, the TBI is a mild TBI. In a further aspect, the TBI is amoderate to severe TBI. The compounds can, in various aspects, cause adetectable improvement in, or a reduction in the progression of, one ormore of the following symptoms of TBI: headache, memory problems,attention deficits, mood swings and frustration, fatigue, visualdisturbances, memory loss, poor attention/concentration, sleepdisturbances, dizziness/loss of balance, irritability, emotionaldisturbances, feelings of depression, seizures, nausea, loss of smell,sensitivity to light and sounds, mood changes, getting lost or confused,or slowness in thinking.

In various aspects, the method comprises administering to the subjecthaving an injury to the nervous system an effective amount of a compoundrepresented by the following formula:

wherein R¹ is selected from hydrogen and C1-C4 alkyl; wherein R² isselected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; wherein each of R³ and R⁴ isindependently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl; or wherein R³ and R⁴ join together to form a ring having 5-7atoms; wherein each of R⁵ and R⁶ is independently selected fromhydrogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; or wherein R⁵ and R⁶join together to form a ring having 5-7 atoms; and wherein R⁷ isselected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; or a pharmaceutically-acceptablesalt thereof.

In one aspect, R¹ is selected from hydrogen and methyl, ethyl, n-propyl,isopropyl, ethenyl, n-propenyl, isopropenyl, —CH₂F, —CH₂Cl, —CH₂CH₂F,—CH₂CH₂Cl, —CH₂CH₂CH₂F, —CH₂CH₂CH₂Cl, —CH(CH₃)CH₂F, —CH(CH₃)CH₂Cl,—CH₂CN, —CH₂CH₂CN, —CH₂CH₂CH₂CN, —CH(CH₃)CH₂CN, —CH₂OH, —CH₂CH₂OH,—CH₂CH₂CH₂OH, —CH(CH₃)CH₂OH, —CH₂NH₂, —CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂, and—CH(CH₃)CH₂NH₂.

In a further aspect, each of R² and R⁷ is independently selected fromhydrogen, —F, —Cl, —Br, —I, —CN, —NH₂, —OH, —NO₂, methyl, ethyl,n-propyl, isopropyl, ethenyl, n-propenyl, isopropenyl, —CH₂F, —CH₂Cl,—CH₂CH₂F, —CH₂CH₂Cl, —CH₂CH₂CH₂F, —CH₂CH₂CH₂Cl, —CH(CH₃)CH₂F,—CH(CH₃)CH₂Cl, —CH₂CN, —CH₂CH₂CN, —CH₂CH₂CH₂CN, —CH(CH₃)CH₂CN, —CH₂OH,—CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH(CH₃)CH₂OH, —OCF₃, —OCH₂CF₃, —OCH₂CH₂CF₃,—OCH(CH₃)CF₃, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃, —NHCH₃,—NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂,—N(CH₂CH₂CH₃)₂, —N(CH(CH₃)CH₃)₂, —N(CH₃)(CH₂CH₃), —CH₂NH₂, —CH₂CH₂NH₂,—CH₂CH₂CH₂NH₂, and —CH(CH₃)CH₂NH₂.

In a still further aspect, each of R³, R⁴, R⁵, and R⁶ is independentlyselected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. Ina still further aspect, each of R³, R⁴, R⁵, and R⁶ is independentlyselected from hydrogen, methyl, ethyl, n-propyl, isopropyl, ethenyl,n-propenyl, isopropenyl, —CH₂F, —CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl,—CH₂CH₂CH₂F, —CH₂CH₂CH₂Cl, —CH(CH₃)CH₂F, —CH(CH₃)CH₂Cl, —CH₂CN,—CH₂CH₂CN, —CH₂CH₂CH₂CN, —CH(CH₃)CH₂CN, —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH,—CH(CH₃)CH₂OH, —OCF₃, —OCH₂CF₃, —OCH₂CH₂CF₃, —OCH(CH₃)CF₃, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃, —NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃,—NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, —N(CH₂CH₂CH₃)₂, —N(CH(CH₃)CH₃)₂,—N(CH₃)(CH₂CH₃), —CH₂NH₂, —CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂, and —CH(CH₃)CH₂NH₂.

In another aspect, R³ and R⁴ and/or R⁵ and R⁶ can join together to forma ring having 5-7 atoms. Thus, for example, the compound can berepresented by the formula:

wherein each n and m is independently an integer ranging from 1-3; eachof R⁸ and R⁹ is independently selected from hydrogen, halogen, —CN,—NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In afurther aspect, each of R⁸ and R⁹ is independently selected fromhydrogen, —F, —Cl, —Br, —I, —CN, —NH₂, —OH, —NO₂, methyl, ethyl,n-propyl, isopropyl, ethenyl, n-propenyl, isopropenyl, —CH₂F, —CH₂Cl,—CH₂CH₂F, —CH₂CH₂Cl, —CH₂CH₂CH₂F, —CH₂CH₂CH₂Cl, —CH(CH₃)CH₂F,—CH(CH₃)CH₂Cl, —CH₂CN, —CH₂CH₂CN, —CH₂CH₂CH₂CN, —CH(CH₃)CH₂CN, —CH₂OH,—CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH(CH₃)CH₂OH, —OCF₃, —OCH₂CF₃, —OCH₂CH₂CF₃,—OCH(CH₃)CF₃, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃, —NHCH₃,—NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂,—N(CH₂CH₂CH₃)₂, —N(CH(CH₃)CH₃)₂, —N(CH₃)(CH₂CH₃), —CH₂NH₂, —CH₂CH₂NH₂,—CH₂CH₂CH₂NH₂, and —CH(CH₃)CH₂NH₂.

In one aspect, each of R¹, R⁴, and R⁵ is independently selected fromhydrogen, methyl, ethyl, and propyl; each of R² and R⁷ is independentlyselected from hydrogen and halogen; and each of R³ and R⁶ is hydrogen.

In a further aspect, each of R¹, R⁴, and R⁵ is methyl; each of R² and R⁷is independently selected from hydrogen and halogen; and each of R³ andR⁶ is hydrogen.

In a still further aspect, each of R¹, R⁴, and R⁵ is independentlyselected from hydrogen, methyl, ethyl, and propyl; and each of R², R³,R⁶, and R⁷ is hydrogen.

Non-limiting examples of compounds that can be administered to thesubject, which have hydrogen or C1-C4 substitutions at R¹ include thefollowing. The C1-C4 substituents at R¹, when present, can be optionallysubstituted as described above.

Non-limiting examples of compounds suitable for administration to asubject, which have substitutions at R² and/or R⁷ include the following:

Non-limiting examples of compounds suitable for administration to asubject, which have a halogen at R² and/or R⁷ include the following:

Non-limiting examples of compounds substituted at R³-R⁶ which aresuitable for administration to a subject include the following:

According to one aspect, the compound administered to the subject totreat an injury to the nervous system is represented by the formula:

The compound shown above corresponds to a racemic mixture of boldine.Boldine is a naturally-occurring alkaloid present in the leaves and barkof Boldo (Peumus boldus Molina), a tree native to the central region ofChile, among other plants.

In various aspects, the compounds administered to the subject have atleast one chiral center and can be substantially free of other isomers(e.g., as a pure or substantially pure optical isomer having a specifiedactivity), or may be admixed, for example, with racemates or otherstereoisomers. In one aspect, the compound can be substantiallyenantiomerically pure. For example, the S enantiomer of boldine can besubstantially free of or separated from the R enantiomer of boldine.Similarly, for example, the R enantiomer of boldine can be substantiallyfree of or separated from the S enantiomer of boldine. In one aspect,the compound can be about 80% enantiomerically pure, about 85%enantiomerically pure, about 90% enantiomerically pure, about 91%enantiomerically pure, about 92% enantiomerically pure, about 93%enantiomerically pure, about 94% enantiomerically pure, about 95%enantiomerically pure, about 96% enantiomerically pure, about 97%enantiomerically pure, about 98% enantiomerically pure, about 99%enantiomerically pure, or about 100% enantiomerically pure.

In one exemplary aspect, the compound administered to the subject totreat an injury to the nervous system is represented by the followingformula:

The compound shown above is the S enantiomer of boldine (also known bythe IUPAC name,(S)-1,10-dimethoxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2,9-diol).S-boldine, when present, can be substantially free of other isomers(e.g., as a pure or substantially pure optical isomer having a specifiedactivity), or may be admixed, for example, with racemates or otherstereoisomers. In one aspect, S-boldine, when present, can be about 80%enantiomerically pure, about 85% enantiomerically pure, about 90%enantiomerically pure, about 91% enantiomerically pure, about 92%enantiomerically pure, about 93% enantiomerically pure, about 94%enantiomerically pure, about 95% enantiomerically pure, about 96%enantiomerically pure, about 97% enantiomerically pure, about 98%enantiomerically pure, about 99% enantiomerically pure, or about 100%enantiomerically pure.

In a further aspect, the method comprises improving voluntary musclecontrol in a subject having an injury to the nervous system, comprisingadministering to the subject an effective amount of a compoundrepresented by the following formula:

wherein R¹ is selected from hydrogen and C1-C4 alkyl; wherein R² isselected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; wherein each of R³ and R⁴ isindependently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl; or wherein R³ and R⁴ join together to form a ring having 5-7atoms; wherein each of R⁵ and R⁶ is independently selected fromhydrogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; or wherein R⁵ and R⁶join together to form a ring having 5-7 atoms; and wherein R⁷ isselected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; or a pharmaceutically-acceptablesalt thereof.

In a further aspect, the method comprises improving voluntary musclecontrol in a subject having an injury to the nervous system, comprisingadministering to the subject an effective amount of a compoundrepresented by the following formula:

In a still further aspect, the method comprises improving voluntarymuscle control in a subject having an injury to the nervous system,comprising administering to the subject an effective amount of S-boldine(or a pharmaceutically-acceptable salt thereof), which corresponds tothe following structural formula:

In one aspect, the method comprises treating neuropathic pain in asubject having an injury to the nervous system, comprising administeringto the subject an effective amount of a compound represented by theformula:

wherein R¹ is selected from hydrogen and C1-C4 alkyl; wherein R² isselected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; wherein each of R³ and R⁴ isindependently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl; or wherein R³ and R⁴ join together to form a ring having 5-7atoms; wherein each of R⁵ and R⁶ is independently selected fromhydrogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; or wherein R⁵ and R⁶join together to form a ring having 5-7 atoms; and wherein R⁷ isselected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; or a pharmaceutically-acceptablesalt thereof.

In a further aspect, the method comprises treating neuropathic pain in asubject having an injury to the nervous system, comprising administeringto the subject an effective amount of a compound represented by theformula:

In a still further aspect, the method comprises treating neuropathicpain in a subject having an injury to the nervous system, comprisingadministering to the subject an effective amount of S-boldine (or apharmaceutically-acceptable salt thereof), which corresponds to thefollowing structural formula:

The compounds and pharmaceutically acceptable salts thereof can beadministered to the subject having an injury to the nervous system via avariety of routes. Non-limiting examples include oral administration(e.g., as a tablet, capsule, lozenge, or troche) or intravenousadministration of the compound together with apharmaceutically-acceptable carrier.

The effective amount or dosage of the composition or an ingredientthereof can vary within wide limits. Such a dosage is adjusted to theindividual requirements in each particular case including the specificcomposition(s) being administered and the condition being treated, aswell as the subject being treated. In general, single dose compositionscan contain such amounts or submultiples thereof of the composition tomake up the daily dose. The dosage can be adjusted by the individualphysician in the event of any contraindications. Dosage can vary, andcan be administered in one or more dose administrations daily, for oneor several days. In some aspects, the effective amount is atherapeutically effective amount. In a further aspect, the effectiveamount is a prophylactically effective amount.

In one aspect, the compounds can be administered to the subject havingan injury to the nervous system in an amount ranging from about 1 mg/kgbody weight to about 500 mg/kg body weight, using a 75 kg human as thesubject. Dosages can be adjusted accordingly depending on the bodyweight of the subject. In a further aspect, the compounds can beadministered to the subject having a nerve injury (e.g., peripheralnerve injury, spinal cord injury (SCI), or spinal cord contusion) in anamount ranging from about 1 mg/kg body weight to about 200 mg/kg bodyweight, using a 75 kg human as the subject.

In a further aspect, the compounds can be administered to the subjecthaving a nerve injury (e.g., peripheral nerve injury, spinal cord injury(SCI), or spinal cord contusion) in an amount ranging from about 1 mg/kgbody weight to about 100 mg/kg body weight, using a 75 kg human as thesubject. In a further aspect, the compounds can be administered to thesubject having a nerve injury (e.g., peripheral nerve injury, spinalcord injury (SCI), or spinal cord contusion) in an amount ranging fromabout 1 mg/kg body weight to about 50 mg/kg body weight, using a 75 kghuman as the subject. In a further aspect, the compounds can beadministered to the subject having a nerve injury (e.g., peripheralnerve injury, spinal cord injury (SCI), or spinal cord contusion) in anamount ranging from about 1 mg/kg body weight to about 25 mg/kg bodyweight, using a 75 kg human as the subject. In a further aspect, thecompounds can be administered to the subject having a nerve injury(e.g., peripheral nerve injury, spinal cord injury (SCI), or spinal cordcontusion) in an amount ranging from about 1 mg/kg body weight to about10 mg/kg body weight, using a 75 kg human as the subject.

In a further aspect, the compounds can be administered to the subjecthaving a nerve injury (e.g., peripheral nerve injury, spinal cord injury(SCI), or spinal cord contusion) in an amount ranging from about 1 mg/kgbody weight to about 5 mg/kg body weight, using a 75 kg human as thesubject. In a further aspect, the compounds can be administered to thesubject having a nerve injury (e.g., peripheral nerve injury, spinalcord injury (SCI), or spinal cord contusion) in an amount ranging fromabout 1 mg/kg body weight to about 4 mg/kg body weight, using a 75 kghuman as the subject.

In one aspect, when the subject suffers from an injury to the nervoussystem such as a spinal cord injury (SCI) or spinal cord contusion, thecompounds can be administered to the subject via intravenousadministration up to 24 hours after the injury to the nervous system. Ina further aspect, the compounds can be administered to the subject overa longer period of time, e.g., days, months, or years, for examplethrough an oral dosage form.

In one aspect, the subject to be treated is a mammal. In a furtheraspect, the subject is a human. In a still further aspect, the subjecthas been diagnosed with a need for treatment of an injury to the nervoussystem prior to the administering step. In a further aspect, thetreatment method comprises the step of identifying a subject in need oftreatment of an injury to the nervous system prior to the administeringstep.

In one aspect, the subject to be treated suffers from neuropathic pain.Neuropathic pain is often seen in several cases of nervous systeminjuries, including without limitation spinal cord injury (SCI) orspinal cord contusion. In the spinal cord, the spinal thalamic tract(STT) constitutes the major ascending nociceptive pathway. As a resultof sustained spontaneous activity occurring in the periphery, STTneurons in the dorsal horn improve increased response to afferentimpulses, including increased background activity, enlarged receptivefields, and normally harmless tactile stimuli. This phenomenon is calledcentral sensitization. Central sensitization can be an importantmechanism of persistent neuropathic pain. Non-neuronal glial cells andimmune responses play a role in central sensitization.

A typical symptom of neuropathic pain is sensory abnormalities (oftenspontaneous or induced burning pain associated with superimposedlightning components), but pain can be deep and tingling. Othersensations can occur, such as hypersensitivity, hyperalgesia, allodynia(pain from non-noxious stimuli), and hyperalgesia (especiallyunpleasant, excessive pain response). As the CNS is sensitized andremodeled, the symptoms persist and generally persist after the maincause of the symptoms (if one is present) is resolved.

Peripheral nerve injuries also causes reactions in peripheral immunecells and glia at several different anatomical sites. The response isthat macrophages and Schwann cells promote the Wallerian degeneration ofaxotomized nerve fibers distal to the nerve lesion, the immune responsesin dorsal root ganglia (DRGs), and macrophages and lymphocytes driven bysatellite cells. Spinal microglial activation dominates the CNS earlyglial response to peripheral nerve injury followed by astrocyteactivation and proliferation.

In various aspects, the neuropathic chronic pain that can be treatedusing the disclosed compounds can be, for example, pain that lasts for along period of at least one month or longer. As discussed above, thepain can be a result of traumatic injury to the nervous system, such asa spinal cord injury (SCI) or spinal cord contusion or other injury tothe nervous system resulting from trauma instead of disease.

In a further aspect, the compounds can be administered to the subjecthaving an injury to the nervous system to improve voluntary musclecontrol of the subject. In one aspect, the compounds can be administeredto the subject having an injury to the nervous system to improvelocomotor function in the subject. Following administration of boldineor its analogs, locomotor function can be evaluated using methods knownin the art, including those described below in Section E.1.

C. MANUFACTURE OF A MEDICAMENT

In one aspect, disclosed is the use of a compound having the followingformula in the manufacture of a medicament for the treatment of aninjury to the nervous system:

wherein R¹ is selected from hydrogen and C1-C4 alkyl; wherein R² isselected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; wherein each of R³ and R⁴ isindependently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl; or wherein R³ and R⁴ join together to form a ring having 5-7atoms; wherein each of R⁵ and R⁶ is independently selected fromhydrogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; or wherein R⁵ and R⁶join together to form a ring having 5-7 atoms; and wherein R⁷ isselected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; or a pharmaceutically-acceptablesalt thereof.

In a further aspect, disclosed is the use of a compound having thefollowing formula, or a pharmaceutically-acceptable salt thereof, in themanufacture of a medicament for the treatment of an injury to thenervous system:

In a still further aspect, disclosed is the use of a compound having thefollowing formula, or a pharmaceutically-acceptable salt thereof, in themanufacture of a medicament for the treatment of an injury to thenervous system:

In yet a further aspect, disclosed is the use of apharmaceutically-acceptable salt of S-boldine, e.g., S-boldinehydrochloride or another suitable salt as described above, in themanufacture of a medicament for the treatment of an injury to thenervous system in a subject.

In various aspects, the method for the manufacture of a medicamentcomprises combining a therapeutically effective amount of a disclosedcompound with a pharmaceutically acceptable carrier or diluent. In afurther aspect, disclosed is a method for the manufacture of amedicament for treating an injury to the nervous system in a subject,the method comprising combining a therapeutically effective amount of adisclosed compound with a pharmaceutically acceptable carrier ordiluent.

According to one aspect, the injury to the nervous system is a centralnervous system injury or a peripheral nervous system injury. In afurther aspect, the injury to the nervous system is a spinal cord injury(SCI), spinal cord contusion, nerve crush injury, or traumatic braininjury (TBI). In a still further aspect, a symptom of the injury to thenervous system is neuropathic pain, loss of voluntary muscle control,loss of locomotor function, or a combination thereof.

D. KITS

In a further aspect, disclosed is a kit comprising a compound having thefollowing formula and instructions for the use thereof for the treatmentof an injury to the nervous system in a subject:

wherein R¹ is selected from hydrogen and C1-C4 alkyl; wherein R² isselected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; wherein each of R³ and R⁴ isindependently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl; or wherein R³ and R⁴ join together to form a ring having 5-7atoms; wherein each of R⁵ and R⁶ is independently selected fromhydrogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; or wherein R⁵ and R⁶join together to form a ring having 5-7 atoms; and wherein R⁷ isselected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; or a pharmaceutically-acceptablesalt thereof.

In another aspect, disclosed is a kit comprising a compound having thefollowing formula, or a pharmaceutically-acceptable salt thereof, andinstructions for the use thereof for the treatment of an injury to thenervous system in a subject:

In another aspect, disclosed is a kit comprising a compound having thefollowing formula, or a pharmaceutically-acceptable salt thereof, andinstructions for the use thereof for the treatment of an injury to thenervous system in a subject:

In yet a further aspect, disclosed is a kit comprising apharmaceutically-acceptable salt of S-boldine, e.g., S-boldinehydrochloride or another suitable salt as described above, andinstructions for the use thereof for the treatment of an injury to thenervous system in a subject.

In various aspects, the compounds or a pharmaceutically-acceptable saltthereof, and the instructions for the use thereof for the treatment ofan injury to the nervous system can be co-packaged. In a still furtheraspect, the compound or pharmaceutically-acceptable salt thereof and theinstructions are not co-packaged.

The kits can also comprise compounds and/or products co-packaged,co-formulated, and/or co-delivered with other components. For example, adrug manufacturer, a drug reseller, a physician, a compounding shop, ora pharmacist can provide a kit comprising a disclosed compound and/orproduct and another component for delivery to a patient.

It is understood that the disclosed kits can be prepared from thedisclosed compounds and pharmaceutical formulations. It is alsounderstood that the disclosed kits can be employed in connection withthe disclosed methods of using the compounds and pharmaceuticalformulations.

According to one aspect, the injury to the nervous system is a centralnervous system injury or a peripheral nervous system injury. In afurther aspect, the injury to the nervous system is a spinal cord injury(SCI), spinal cord contusion, nerve crush injury, or traumatic braininjury (TBI). In a still further aspect, a symptom of the injury to thenervous system is neuropathic pain, loss of voluntary muscle control,loss of locomotor function, or a combination thereof.

E. EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how themethods and products claimed herein are made and evaluated, and areintended to be purely exemplary and are not intended to limit the scopeof what the inventors regard as their invention. Efforts have been madeto ensure accuracy with respect to numbers (e.g., amounts, temperature,etc.), but some errors and deviations should be accounted for. Unlessindicated otherwise, parts are parts by weight, temperature is in ° C.or is at ambient temperature, and pressure is at or near atmospheric.The Examples are provided herein to illustrate the invention, and shouldnot be construed as limiting the invention in any way.

1. Functional Recovery after Boldine Treatment

With references to FIGS. 1A-C, oral administration of boldine to 3-monthold C57BL6 mice that have undergone a moderate contusion spinal cordinjury (SCI), achieved after a 50 kdyn impact contusion at T9-T10,significantly improves locomotor function. Function was determined bybehavioral testing using both the Basso Mouse Scale (BMS) score (FIG.1A) and the ladder rung walk test (LRWT) (FIG. 1B). A timeline for thesestudies is shown in FIG. 1C. While sham mice had normal BMS scores a fewdays after laminectomy, the BMS scores for contusion-SCI mice were muchlower. Twice daily boldine treatment starting at 4-dpi significantlyincreased BMS scores at 13 dpi (FIG. 1A). Analysis of LRWT done at13-dpi showed that boldine-treated mice had many fewer incorrect steps(13%) than vehicle-treated SCI mice (83%) (FIG. 1B). (N=5; ANOVA *p<0.05and **p<0.005 respectively).

2. Reduction in Hippocampal mRNA Levels for Caspase-1 and Il-1B afterSCI Following Boldine Treatment

In rats, a spinal cord injury (SCI) can result in cognitive deficitsthat are associated with activation in brain regions linked to painprocessing and cognition of microglia and astrocytes as well asassociated with upregulation of a gene involved in inflammation (Wu etal. 2013; Wu et al. 2014). Such changes may drive central pain inneuropathic pain syndromes. To determine whether boldine mitigates suchchanges, mRNA expression of Cx43 and genes involved in inflammasomeassembly and activity were determined in mouse brains. While SCIincreased caspase-1 in the hippocampus. This change appeared to becorrected by boldine (FIG. 2). Similarly, boldine significantly reducedmRNA levels of IL-1β by 65.5%, and CCL2 in 47.2% when compared to mRNAlevels of vehicle-treated animals after contusion SCI (N=3, * p<0.05 byone-way ANOVA) (FIG. 3). These studies indicate that boldine can reduceneuropathic pain following spinal cord injury (SCI) associated withreductions in brain and spinal cord of expression of pro-inflammatorycytokines and chemokines linked to pathological pain.

3. RNA Sequence Analysis

Additional studies were performed using tissues harvested from the micefor which behavioral testing data showing effects of boldine on BassoMouse Scale and ladder rung walk test were collected. RNA-seq analysiswas performed on spinal cord segments from SCI mice at 14-dpi treatedwith boldine or vehicle starting at 4-dpi (N=3 for each). Differentiallyexpressed genes (DEGs) were clustered by their gene ontology (GO) andenrichment of GO terms was tested using a Fisher's exact test (GeneSCFv1.1-p2). Enriched DEGs were involved in pathways related to neutrophilactivation and aggregation, inflammatory responses and astrocytedevelopment.

Genes from a list of the top DEGs from the RNA-seq analysis wereconsidered and tested for differences in gene expression ofpro-inflammatory chemokines Ccl2 and Ccl3 between vehicle and boldinetreated spinal cord tissues from C57B6 SCI animals at 14-dpi.Laminectomy-only (Sham) animals as were used as controls. Levels of bothchemokines were significantly increased at 14-dpi in SCI vehicle-treatedanimals compared to shams (N=3 ANOVA *p<0.05). Boldine resulted in anapparent decrease which did not reach our threshold for significance(N=3 ANOVA p=0.091 and p=0.085, respectively). These results areconsistent with the bulk RNA-seq data.

4. Immunofluorescence Staining Studies

Immunofluorescence staining was performed on injured spinal cords ofvehicle and boldine treated SCI mice at 14-dpi. 30-micron transversesections were used to evaluate differences in the labeling of theneurite outgrowth marker GAP-43. GAP43 immunofluorescence wasdramatically increased in sections from boldine treated compared tovehicle animals.

5. Reduction of mRNA Levels of CCL2

To model effects of boldine on release of chemokines and othermediators, changes in mRNA expression after lipopolysaccharide(LPS)-induced inflammatory responses were analyzed using astrocyticprimary cell cultures. These studies show that boldine treatment of LPSastrocytes significantly reduces mRNA levels of CCL2 by 38% compared tomRNA levels of vehicle-treated LPS astrocytes.

It will be apparent to those skilled in the art that variousmodifications and variations can be made without departing from thescope or spirit of this disclosure. Other embodiments will be apparentto those skilled in the art from consideration of the specification andpractice disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritbeing indicated by the following claims.

What is claimed is:
 1. A method of treating an injury to the nervous system in a subject, comprising administering to the subject an effective amount of a compound represented by the formula:

wherein R¹ is selected from hydrogen and C1-C4 alkyl; wherein R² is selected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R³ and R⁴ is independently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; or wherein R³ and R⁴ join together to form a ring having 5-7 atoms; wherein each of R⁵ and R⁶ is independently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; or wherein R⁵ and R⁶ join together to form a ring having 5-7 atoms; and wherein R⁷ is selected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; or a pharmaceutically-acceptable salt thereof, thereby treating the injury to the nervous system in the subject.
 2. The method of claim 1, wherein each of R¹, R⁴, and R⁵ is independently selected from hydrogen, methyl, ethyl, and propyl; wherein each of R² and R⁷ is independently selected from hydrogen and halogen; and wherein each of R³ and R⁶ is hydrogen.
 3. The method of claim 1, wherein each of R¹, R⁴, and R⁵ is methyl; wherein each of R² and R⁷ is independently selected from hydrogen and halogen; and wherein each of R³ and R⁶ is hydrogen.
 4. The method of claim 1, wherein each of R¹, R⁴, and R⁵ is independently selected from hydrogen, methyl, ethyl, and propyl; and wherein each of R², R³, R⁶, and R⁷ is hydrogen.
 5. The method of claim 1, wherein the compound is represented by the formula:


6. The method of claim 1, wherein the injury to the nervous system is a spinal cord injury (SCI), spinal cord contusion, nerve crush injury, or traumatic brain injury (TBI).
 7. The method of claim 1, wherein a symptom of the injury to the nervous system is neuropathic pain.
 8. A method of improving voluntary muscle control in a subject having an injury to the nervous system, comprising administering to the subject an effective amount of a compound represented by the formula:

wherein R¹ is selected from hydrogen and C1-C4 alkyl; wherein R² is selected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R³ and R⁴ is independently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; or wherein R³ and R⁴ join together to form a ring having 5-7 atoms; wherein each of R⁵ and R⁶ is independently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; or wherein R⁵ and R⁶ join together to form a ring having 5-7 atoms; and wherein R⁷ is selected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; or a pharmaceutically-acceptable salt thereof, thereby improving voluntary muscle control in the subject.
 9. The method of claim 8, wherein each of R¹, R⁴, and R⁵ is independently selected from hydrogen, methyl, ethyl, and propyl; wherein each of R² and R⁷ is independently selected from hydrogen and halogen; and wherein each of R³ and R⁶ is hydrogen.
 10. The method of claim 8, wherein each of R¹, R⁴, and R⁵ is methyl; wherein each of R² and R⁷ is independently selected from hydrogen and halogen; and wherein each of R³ and R⁶ is hydrogen.
 11. The method of claim 8, wherein each of R¹, R⁴, and R⁵ is independently selected from hydrogen, methyl, ethyl, and propyl; and wherein each of R², R³, R⁶, and R⁷ is hydrogen.
 12. The method of claim 8, wherein the compound is represented by the formula:


13. The method of claim 8, wherein the injury to the nervous system is a spinal cord injury (SCI), spinal cord contusion, nerve crush injury, or traumatic brain injury (TBI).
 14. The method of claim 8, wherein a symptom of the injury to the nervous system is neuropathic pain.
 15. The method of claim 8, wherein improving voluntary muscle control comprises improving locomotor function.
 16. A method of treating neuropathic pain in a subject having an injury to the nervous system, comprising administering to the subject an effective amount of a compound represented by the formula:

wherein R¹ is selected from hydrogen and C1-C4 alkyl; wherein R² is selected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R³ and R⁴ is independently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; or wherein R³ and R⁴ join together to form a ring having 5-7 atoms; wherein each of R⁵ and R⁶ is independently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; or wherein R⁵ and R⁶ join together to form a ring having 5-7 atoms; and wherein R⁷ is selected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; or a pharmaceutically-acceptable salt thereof, thereby treating neuropathic pain in the subject.
 17. The method of claim 16, wherein each of R¹, R⁴, and R⁵ is independently selected from hydrogen, methyl, ethyl, and propyl; wherein each of R² and R⁷ is independently selected from hydrogen and halogen; and wherein each of R³ and R⁶ is hydrogen.
 18. The method of claim 16, wherein each of R¹, R⁴, and R⁵ is methyl; wherein each of R² and R⁷ is independently selected from hydrogen and halogen; and wherein each of R³ and R⁶ is hydrogen.
 19. The method of claim 16, wherein each of R¹, R⁴, and R⁵ is independently selected from hydrogen, methyl, ethyl, and propyl; and wherein each of R², R³, R⁶, and R⁷ is hydrogen.
 20. The method of claim 16, wherein the compound is represented by the formula:


21. The method of claim 16, wherein the injury to the nervous system is a spinal cord injury (SCI), spinal cord contusion, nerve crush injury, or traumatic brain injury (TBI). 